Corneal confocal microscopy detects early nerve regeneration after pharmacological and surgical interventions: Systematic review and meta-analysis.

Corneal confocal microscopy (CCM) is an ophthalmic imaging technique that enables the identification of corneal nerve fibre degeneration and regeneration. To undertake a systematic review and meta-analysis of studies utilizing CCM to assess for corneal nerve regeneration after pharmacological and surgical interventions in patients with peripheral neuropathy. Databases (EMBASE [Ovid], PubMed, CENTRAL and Web of Science) were searched to summarize the evidence from randomized and non-randomized studies using CCM to detect corneal nerve regeneration after pharmacological and surgical interventions. Data synthesis was undertaken using RevMan web. Eighteen studies including 958 patients were included. CCM identified an early (1-8 months) and longer term (1-5 years) increase in corneal nerve measures in patients with peripheral neuropathy after pharmacological and surgical interventions. This meta-analysis confirms the utility of CCM to identify nerve regeneration following pharmacological and surgical interventions. It could be utilized to show a benefit in clinical trials of disease modifying therapies for peripheral neuropathy.

Self-Organization of Lipid-Porphyrin Conjugates at the Air/Water Interface.

Lipid-porphyrin conjugates are versatile compounds which can self-assemble into liposome-like structures with multifunctional properties. Most of the conjugates that have been described so far, consisted in grafting pyropheophorbide-a (Pyro-a) or other porphyrin derivatives through the esterification of the hydroxyl group in the sn-2 position of a lysophosphatidylcholine. However, despite the versatility of these conjugates, less is known about the impact of the lipid backbone structure on their 2D phase behavior at the air/water interface and more precisely on their fine structures normal to the interface as well as on their in-plane organization. Herein, we synthesized a new lipid-porphyrin conjugate (PyroLSM) based on the amide coupling of Pyro-a to a lysosphingomyelin backbone (LSM) and we compared its interfacial behavior to that of Pyro-a and Pyro-a conjugated lysophosphatidylcholine (PyroLPC) using Langmuir balance combined to a variety of other physical techniques. Our results provided evidence on the significant impact of the lipid backbone on the lateral packing of the conjugates as well as on the shape and size of the formed domains. Compared to Pyro-a and PyroLPC monolayers, PyroLSM exhibited the highest lateral packing which highlights the role of the lipid backbone in controlling their 2D organization which in turn may impact the photophysical properties of their assemblies.

Incidence and risk factors of bladder injury during cesarean delivery: a cohort study.

PURPOSE: To identify risk factors associated with bladder injury during cesarean delivery, and to determine the frequency of associated morbidities. METHODS: Data obtained from the United States' Health Care Cost and Utilization Project-Nationwide Inpatient Sample were used to conduct a retrospective population-wide cohort study. ICD-9 codes were used to identify women who underwent a cesarean delivery between 1999 and 2015. Subsequently, women were classified based on whether or not they experienced a bladder injury during delivery. Multivariate logistic regression was used to determine predictors of bladder injury in cesarean deliveries and to examine the associated morbidities while adjusting for baseline maternal demographics and clinical characteristics. RESULTS: Of 4,169,681 cesarean deliveries identified, there were 7,627 (0.2%) bladder injuries for an overall incidence of 18 per 10,000. Women ≥ 35 years were at greater risk of bladder injury 1.5 (1.4-1.6), as were women with endometriosis 2.0 (1.5-2.7) and Crohn's disease 2.7 (1.7-4.2). Risk of bladder injury increased if the cesarean delivery was associated with placenta previa 2.2 (1.9-2.4), previous cesarean delivery 4.3 (4.1-4.6), failed instrumental delivery 4.1 (3.5-4.8), fetal distress 1.7 (1.6-1.8), failed trial of labor after cesarean delivery 1.3 (1.2-1.4), and labor dystocia 1.7 (1.6-1.8). Cesarean hysterectomies presented the greatest risk for bladder injury 37.0 (33.7-40.6). Bladder injury was associated with an increased frequency of sepsis, venous thromboembolism, peritonitis, blood transfusions and longer hospital stays. CONCLUSION: Bladder injury during cesarean deliveries is a rare outcome but it is more common among women with certain demographic and clinical characteristics. Among these cases, strategies to prevent sepsis and venous thromboembolism should be considered.

A Polymer Prodrug Strategy to Switch from Intravenous to Subcutaneous Cancer Therapy for Irritant/Vesicant Drugs.

Chemotherapy is almost exclusively administered via the intravenous (IV) route, which has serious limitations (e.g., patient discomfort, long hospital stays, need for trained staff, high cost, catheter failures, infections). Therefore, the development of effective and less costly chemotherapy that is more comfortable for the patient would revolutionize cancer therapy. While subcutaneous (SC) administration has the potential to meet these criteria, it is extremely restrictive as it cannot be applied to most anticancer drugs, such as irritant or vesicant ones, for local toxicity reasons. Herein, we report a facile, general, and scalable approach for the SC administration of anticancer drugs through the design of well-defined hydrophilic polymer prodrugs. This was applied to the anticancer drug paclitaxel (Ptx) as a worst-case scenario due to its high hydrophobicity and vesicant properties (two factors promoting necrosis at the injection site). After a preliminary screening of well-established polymers used in nanomedicine, polyacrylamide (PAAm) was chosen as a hydrophilic polymer owing to its greater physicochemical, pharmacokinetic, and tumor accumulation properties. A small library of Ptx-based polymer prodrugs was designed by adjusting the nature of the linker (ester, diglycolate, and carbonate) and then evaluated in terms of rheological/viscosity properties in aqueous solutions, drug release kinetics in PBS and in murine plasma, cytotoxicity on two different cancer cell lines, acute local and systemic toxicity, pharmacokinetics and biodistribution, and finally their anticancer efficacy. We demonstrated that Ptx-PAAm polymer prodrugs could be safely injected subcutaneously without inducing local toxicity while outperforming Taxol, the commercial formulation of Ptx, thus opening the door to the safe transposition from IV to SC chemotherapy.

Degradable Glycopolyester-like Nanoparticles by Radical Ring-Opening Polymerization.

A small library of degradable polyester-like glycopolymers was successfully prepared by the combination of radical ring-opening copolymerization of 2-methylene-1,3-dioxepane as a cyclic ketene acetal (CKA) with vinyl ether (VE) derivatives and a Pd-catalyzed thioglycoconjugation. The resulting thioglycopolymers were formulated into self-stabilized thioglyconanoparticles, which were stable up to 4 months and were enzymatically degraded. Nanoparticles and their degradation products exhibited a good cytocompatibility on two healthy cell lines. Interactions between thioglyconanoparticles and lectins were investigated and highlighted the presence of both specific carbohydrate/lectin interactions and nonspecific hydrophobic interactions. Fluorescent thioglyconanoparticles were also prepared either by encapsulation of Nile red or by the functionalization of the polymer backbone with rhodamine B. Such nanoparticles were used to prove the cell internalization of the thioglyconanoparticles by lung adenocarcinoma (A549) cells, which underlined the great potential of P(CKA-co-VE) copolymers for biomedical applications.

Novel [l,2,4]triazolo[3,4-a]isoquinoline chalcones as new chemotherapeutic agents: Block IAP tyrosine kinase domain and induce both intrinsic and extrinsic pathways of apoptosis.

Two novel chemotherapeutic chalcones were synthesized and their structures were confirmed by different spectral tools. Theoretical studies such as molecular modeling were done to detect the mechanism of action of these compounds. In vitro cytotoxicity showed a strong effect against all tested cell lines (MCF7, A459, HepG2, and HCT116), and low toxic effect against normal human melanocytes (HFB4). The lung carcinoma cell line was chosen for further molecular studies. Real-time PCR demonstrated that the two compounds upregulated gene expression of (BAX, p53, casp-3, casp-8, casp-9) genes and decreased the expression of anti-apoptotic genes bcl2, CDK4, and MMP1. Flow-cytometry indicated that cell cycle arrest of A459 was induced at the G2/M phase and the apoptotic percentage increased significantly compared to the control sample. Cytochrome c oxidase and VEGF enzyme activity were detected by ELISA assay. SEM tool was used to follow the morphological changes that occurred on the cell surface, cell granulation, and average roughness of the cell surface. The change in the number and morphology of mitochondria, cell shrinkage, increase in the number of cytoplasmic organelles, membrane blebbing, chromatin condensation, and apoptotic bodies were observed using TEM. The obtained data suggested that new chalcones exerted their pathways on lung carcinoma through induction of two pathways of apoptosis. Graphical abstract Novel chalcones were prepared and confirmed by different spectral tools. Docking simulations were done to detect the mechanism of action. In vitro cytotoxicity indicated a strong effect against different cancer cell lines and low toxic effects against normal human melanocytes (HFB4). The lung carcinoma cell line was chosen for further molecular studies that include Real-time PCR, Flow-cytometry, Cytochrome c oxidase, and ELISA assay. SEM and TEM tool were used to follow the morphological changes occurred on the cell surface.

Design and Synthesis of New PEGylated Polydopamine-Based Nanoconstructs Bearing ROS-Responsive Linkers and a Photosensitizer for Bimodal Photothermal and Photodynamic Therapies against Cancer.

Polydopamine (PDA) nanoparticles (NPs) have recently acquired considerable attention for the development of nanoplatforms with multifunctional properties including photothermal (PTT) and photodynamic (PDT) activities. In addition to their high PTT performance, they can be easily conjugated to different types of photosensitizers (PSs) to acquire PDT activity. However, because of PDA free-radical scavenging properties, grafting the PSs directly to PDA surfaces may lead to an inefficient PDT outcome. Thus, the present work aims at synthesizing and characterizing a new PEGylated PDA-based nanoplatform with bifunctional PTT and PDT properties, which allows bimodal cancer therapy with the possibility to release the PS on demand in a spatiotemporal fashion. To do so, PDA NPs with a well-defined size and shape were prepared by the auto-oxidative self-polymerization process of dopamine hydrochloride in mild alkaline solution. The impact of the size on the PTT conversion efficiency was then determined. This allowed us to choose the optimal PDA NP size for PTT applications. Next, PDA NPs were decorated with SH-PEG polymers that bear at their extremity a thioketal reactive oxygen species-cleavable linker coupled to trisulfonated-tetraphenylporphyrin (TPPS3) chosen as a hydrophilic PS. The grafting efficiency of PS-conjugated PEG on PDA was demonstrated in situ using a quartz crystal microbalance with dissipation monitoring. In addition, the photoinduced release of the PS was demonstrated by 1H NMR. Finally, PTT/PDT bimodal therapy was assessed in vitro on human squamous esophageal cells by illuminating the PDA NPs at two different wavelengths, which showed the strong synergistic effect of combining PTT and PDT within this nanoplatform.

Computational studies and sever apoptotic bioactivity of new heterocyclic cyanoacrylamide based p-fluorophenyl and p-phenolic compounds against liver carcinoma (Hepg2).

An efficient route for the preparation of new heterocyclic cyanoacrylamides based p-fluorophenyl and p-phenolic compounds was depicted. All structures were confirmed based on the different spectral tools and elemental analyses. MTT assay for the novel synthesized series was performed against four different cell lines (A549, MCF7, Hepg2, and Wi38). Among all tested groups, the p-phenolic compound 10 (207.1 µg/ml) and the corresponding p-fluorophenyl derivative 6 (325.7 µg/ml) were selected for further simulation and molecular studies against liver carcinoma. Compounds 6 and 10 were investigated theoretically to different protein sets as (cdk2, Bcl2-xl, cIAP1-BIR3, and MDM2) and they illustrated different binding affinities. The computational studies and different molecular techniques (e.g. cell cycle analysis, DPA assay, relative gene expression, and ELISA assay) were utilized in this report.

Bee venom and its active component Melittin synergistically potentiate the anticancer effect of Sorafenib against HepG2 cells.

There are current attempts to find a safe substitute or adjuvant for Sorafenib (Sorf), the standard treatment for advanced hepatocellular carcinoma (HCC), as it triggers very harsh side effects and drug-resistance. The therapeutic properties of Bee Venom (BV) and its active component, Melittin (Mel), make them suitable candidates as potential anti-cancer agents per-se or as adjuvants for cancer chemotherapy. Hence, this study aimed to evaluate the combining effect of BV and Mel with Sorf on HepG2 cells and to investigate their molecular mechanisms of action. Docking between Mel and different tumor-markers was performed. The cytotoxicity of BV, Mel and Sorf on HepG2 and THLE-2 cells was conducted. Combinations of BV/Sorf and Mel/Sorf were performed in non-constant ratios on HepG2. Expression of major cancer-related genes and oxidative stress status was evaluated and the cell cycle was analyzed. The computational analysis showed that Mel can bind to and inhibit XIAP, Bcl2, MDM2, CDK2 and MMP12. Single treatments of BV, Mel and Sorf on HepG2 showed lower IC50than on THLE-2. All combinations revealed a synergistic effect at a combination index (CI) < 1. Significant upregulation (p < 0.05) of p53, Bax, Cas3, Cas7 and PTEN and significant downregulation (p < 0.05) of Bcl-2, Cyclin-D1, Rac1, Nf-κB, HIF-1a, VEGF and MMP9 were observed. The oxidative stress markers including MDA, SOD, CAT and GPx showed insignificant changes, while the cell cycle was arrested at G2/M phase. In conclusion, BV and Mel have a synergistic anticancer effect with Sorf on HepG2 that may represent a new enhancing strategy for HCC treatment.

Late presentation of extrauterine adenomyomas after laparoscopic morcellation at hysterectomy: a case report.

BACKGROUND: An adenomyoma is a well circumscribed form of adenomyosis and can be located within the myometrium, in the endometrium as a polyp, or extrauterine with the last being the rarest presentation amongst the three. With the ongoing advancement in gynecological surgery, the use of electromechanical morcellators have made the removal of large and dense specimens possible with minimally invasive techniques. However, it has also caused an increase in complications which were previously rare. Whilst the tissue is being grinded within the abdominal cavity, residual tissue can spread and remain inside, allowing for implantation to occur and thereby giving rise to recurrence of uterine tissue as a new late postoperative complication. Case presentation A 45-year-old woman presented with worsening constipation and right iliac fossa pain. Her past surgical history consists of laparoscopic supra-cervical hysterectomy that was indicated due to uterine fibroids. Computerized tomography and magnetic resonance imaging were done, which showed an irregular lobulated heterogeneous mass seen in the presacral space to the right, located on the right lateral aspect of the recto-sigmoid, measuring 4.5 × 4.3 × 4.3 cm in size. A transvaginal ultrasound revealed a cyst in the left ovary. The patient had a treatment course over several months that included Dienogest (progestin) and Goserelin (GnRH analogue) with add-back therapy. In line with the declining response to medications, the patient was advised for a laparoscopic ovarian cystectomy. During the surgery, an additional lesion was found as a suspected fibroid and the left ovarian cyst was identified as pockets of peritoneal fluid which was sent for cytology. The surgical pathology report confirmed adenomyosis in both specimens, namely the right mass and the initially suspected fibroid. CONCLUSION: In this case report, we showcase a rare occurrence of an extrauterine adenomyoma presenting two years post laparoscopic morcellation at hysterectomy. This poses questions regarding the benefits versus risks of power morcellation in laparoscopic hysterectomy.

Rupture Rates Between 2-Strand and 4-Strand Flexor Tendon Repairs: Is Less More?

The purpose of this study was to explore the difference in clinical outcome of 2-strand and 4-strand flexor tendon repairs in a single unit in adult population. A total of 109 complete divisions of a single flexor tendon were analyzed from 2016 to 2018 retrospectively. Thirty flexor tendons were repaired with 2-strand and 79 tendons were repaired with 4-strand technique. There was no significant difference in the complication rate including rupture, infection, and adhesions. These results support that 4-strand is not superior than 2-strand and that lower volume type of repair would be preferable.

Newly Synthesized Lipid-Porphyrin Conjugates: Evaluation of Their Self-Assembling Properties, Their Miscibility with Phospholipids and Their Photodynamic Activity In Vitro.

Lipid-porphyrin conjugates are considered nowadays as promising building blocks for the conception of supramolecular structures with multifunctional properties, required for efficient cancer therapy by photodynamic therapy (PDT). The synthesis of two new lipid-porphyrin conjugates coupling pheophorbide-a (Pheo-a), a photosensitizer derived from chlorophyll-a, to either chemically modified lyso-phosphatidylcholine (PhLPC) or egg lyso-sphingomyelin (PhLSM) is reported. The impact of the lipid backbone of these conjugates on their self-assembling properties, as well as on their physicochemical properties, including interfacial behavior at the air/buffer interface, fluorescence and absorption properties, thermotropic behavior, and incorporation rate in the membrane of liposomes were studied. Finally, their photodynamic activity was evaluated on esophageal squamous cell carcinoma (ESCC) and normal esophageal squamous epithelium cell lines. The liposome-like vesicles resulting from self-assembly of the pure conjugates were unstable and turned into aggregates with undefined structure within few days. However, both lipid-porphyrin conjugates could be efficiently incorporated in lipid vesicles, with higher loading rates than unconjugated Pheo-a. Interestingly, phototoxicity tests of free and liposome-incorporated lipid-porphyrin conjugates demonstrated a better selectivity in vitro to esophageal squamous cell carcinoma relative to normal cells.

Advanced NMR-Based Structural Investigation of Glucosinolates and Desulfoglucosinolates.

Glucosinolates (GLs) constitute a class of plant secondary metabolites that are characteristic of the order Brassicales. They each contain a common hydrophilic moiety connected to a mostly hydrophobic side chain whose constitution is the most frequent structural variant. Their transformations by myrosinases lead to intensively studied and highly reactive compounds of biological relevancy. In other respects, the enzymatic desulfation of GLs produces derivatives (DS-GLs) that are useful for GL analysis. A collection of 31 compounds, GLs and DS-GLs, representing 17 different side chains was established in order to report accurate descriptions of the molecules' 1H-, 13C-, and 15N-NMR parameters. The descriptions of the 1H-NMR spectra were achieved using the PERCH software, which accurately analyzed the complex coupling patterns that arose from strongly coupled nuclei. The chemical shift assignments were supported by 2D COSY, HSQC, and HMBC spectra. The impact of desulfation and the influence of the nature of the side chains on the chemical shift values are discussed. The results of the spectroscopic analysis and the 3D chemical-structure models of the studied molecules were grouped in structure-and-data-format (SDF) files. The NMR parameters were also collected in a simple text file, a spreadsheet file, and a relational database.

Convergent Synthesis of N,S-bis Glycosylquinolin-2-ones via a Pd-G3-XantPhos Precatalyst Catalysis.

Buchwald-Hartwig-Migita cross-coupling of 1-thiosugars with α- or ß-3-iodo-N-glycosylquinolin-2-ones has been accomplished under mild and operationally simple reaction conditions through the use of a Pd-G3 XantPhos palladacycle precatalyst. This new methodology has been successfully applied to a variety of α- or ß-mono-, di-, and poly-thiosugar derivatives to efficiently synthesize a series of α- or ß-N,S-bis-glycosyl quinolin-2-ones, which are difficult to synthesize by classical methods.

Osteonecrosis of the Femoral Head as a Potential Pitfall in 18 F-PSMA-1007 PET.

ABSTRACT: PSMA-targeted PET agents are mainly involved for prostate cancer; however, unspecific bone uptakes can be challenging for the clinician. We report the case of a 71-year-old man with history of recurrent prostate cancer initially treated by surgery and radiation therapy. 18 F-PSMA 1007 PET/CT was performed. Beside hyperfixing lymph nodes, focal uptake was found in right femoral head with shell subchondral hypofixation and no morphologic correlate on CT. MRI found bilateral osteonecrosis of the femoral head. This case emphasizes that osteonecrosis of the femoral head can mimic a metastasis uptake, even with normal CT, without however the fixation being constant.

Filling the void: Morphological and molecular phylogenetic analyses of helminths assemblage from the Egyptian egret Bubulcus ibis.

The cattle egret (B. ibis) as a common wader birds in Egypt, they act a sole reservoir for many parasites and play a vital role in their life cycle and their distribution in their environment. The study was conducted from September 2020 to August 2021. A total of 180 B. ibis were collected from Al Qantara Gharb, Ismailia province, Egypt. Parasite species identification infecting cattle egret included morphological and morphometric characteristics based on light and scanning microscopy. Additionally, utilizing the partial small subunit ribosomal RNA (18S rRNA, ITS2 and ITS1) gene sequence, maximum parsimony was used to infer the phylogeny of the recovered species. The morphological and molecular studies revealed three helminths. Only one nematode (Desportesius invaginatus, linstow,1901) and two trematodes (Patagifer bilobus, Dietz,1909 and Apharyngostrigea cornu, Zeder,1800) have been identified. The cattle egret (B. ibis) are protagonists in the life cycle of many parasites. The study is considered the first in Egypt to fill the gap of phylogenetic analysis of three helminths; two of them (A. cornu and P. bilobus) were the first to be molecular phylogenetically analyzed in Egypt. The molecular data provided set the conspecific relation of the three identified helminths species with other related helminths. The new identified sequences will help in founding the basis for forthcoming identifications of other helminths species from cattle egret in Egypt and prospective view to possible parasitic assemblage affecting egret population and other animal populations in their environment.

Synthesis, cytotoxicity, anti-inflammatory, anti-metastatic and anti-oxidant activities of novel chalcones incorporating 2-phenoxy-N-arylacetamide and thiophene moieties: induction of apoptosis in MCF7 and HEP2 cells.

Eight Novel chalcones were synthesized and their structures were confirmed by different spectral tools. All the prepared compounds were subjected to SRB cytotoxic screening against several cancer cell lines. Compound 5c exerted the most promising effect against MCF7 and HEP2 cells with IC50 values of 9.5 and 12 µg/mL, respectively. Real-time PCR demonstrated the inhibitory effect of compound 5c on the expression level of Antigen kiel 67 (KI-67), Survivin, Interleukin-1beta (IL-1B), Interleukin-6 (IL-6), Cyclooxygenase-2 (COX-2) and Protein kinase B (AKT1) genes. Flow-cytometric analysis of the cell cycle indicated that compound 5c stopped the cell cycle at the G0/G1 and G2/M phases in MCF7 and HEP2 treated cells, respectively. ELISA assay showed that Caspase 8, Caspase 9, P53, BAX, and Glutathione (GSH) were extremely activated and Matrix metalloproteinase 2 (MMP2), Matrix metalloproteinase 9 (MMP9), BCL2, Malondialdehyde (MDA), and IL-6 were deactivated in 5c treated MCF7 and HEP2 cells. Wound healing revealed that chalcone 5c reduced the ability to close the scrape wound and decreased the number of migrating MCF7 and HEP2 cells compared to the untreated cells after 48 h. Theoretical molecular modeling against P53 cancer mutant Y220C and Bcl2 showed binding energies of -22.8 and -24.2 Kcal/mole, respectively, which confirmed our ELISA results.

Novel 3-(pyrazol-4-yl)-2-(1H-indole-3-carbonyl)acrylonitrile derivatives induce intrinsic and extrinsic apoptotic death mediated P53 in HCT116 colon carcinoma.

A novel series of α-cyano indolylchalcones was prepared, and their chemical structures were confirmed based on the different spectral data. Among them, compound 7f was observed to be the most effective bioactive chalcone with distinguished potency and selectivity against colorectal carcinoma (HCT116) with IC50 value (6.76 µg/mL) relative to the positive control (5 FU) (77.15 µg/mL). In a preliminary action study, the acrylonitrile chalcone 7f was found to enhance apoptotic action via different mechanisms like inhibition of some anti-apoptotic protein expression, regulation of some apoptotic proteins, production of caspases, and cell cycle arrest. All mechanisms suggested that compound 7f could act as a professional chemotherapeutic agent. Also, a molecular docking study was achieved on some selected proteins implicated in cancer (Caspase 9, XIAP, P53 mutant Y220C, and MDM2) which showed variable interactions with compound 7f with good Gibbs free energy scores.

A Cross-Sectional Study to Investigate the Prevalence of Self-Medication of Non-Opioid Analgesics Among Medical Students at Qassim University, Saudi Arabia.

Purpose: Self-medication (SM) using non-opioid analgesics (NOA) is contentious and increasingly recognized as a major public health concern with severe consequences, including masking of malignant and fatal diseases, risk of misdiagnosis, problems relating to over- and under-dosing, drug interactions, incorrect dosage, and choice of therapy. Herein, we aim to determine the prevalence of SM with NOA among pharmacy and medical students at Unaizah College, Qassim University, Saudi Arabia. Patients and Methods: A cross-sectional study using a validated self-administered questionnaire was conducted on 709 pharmacy and medicine students belonging to an age group of 21-24 years from Unaizah Colleges. Data were statistically analyzed using SPSS version 21. Results: Of 709 participants, 635 responded to the questionnaire. Our results showed a prevalence percentage of 89.6% using self-medicated NOA for pain management. The most common factor leading to SM in NOA was the mild nature of the illness (50.6%), and headache/migraine (66.8%) was the dominant health problem. Paracetamol (acetaminophen, 73.7%) was the most commonly used analgesic, followed by ibuprofen (16.5%). The most common and reliable sources of drug information were pharmacists (51.5%). Conclusion: We observed a high rate of SM for NOA among undergraduate students. We believe that the adverse consequences of SM could be controlled through educational, regulatory, and administrative strategies by providing appropriate awareness sessions, and the role of pharmacists should be highlighted in preventing SM from NOA.

Design, synthesis, in vitro anticancer, molecular docking and SAR studies of new series of pyrrolo[2,3-d]pyrimidine derivatives.

The current study involves the design and synthesis of a newly synthesized pyrrolo[2,3-d]pyrimidine derivatives to contain chlorine atoms in positions 4 and 6 and trichloromethyl group in position 2 using microwave technique as a new and robust approach for preparation of this type of pyrrolo[2,3-d]pyrimidine derivatives. The chemical structure of the synthesized pyrrolo[2,3-d]pyrimidine derivatives 3-19 was well-characterized using spectral and elemental analyses as well as single-crystal X-ray diffraction. All compounds were tested in vitro against seven selected human cancer cell lines, namely, MCF7, A549, HCT116, PC3, HePG2, PACA2 and BJ1 using MTT assay. It was found that compounds 14a, 16b and 18b were the most active toward MCF7 with IC50 (1.7, 5.7, and 3.4 µg/ml, respectively) relative to doxorubicin (Dox.) (26.1 µg/ml). Additionally, compound 17 exerted promising cytotoxic effects against HePG2 and PACA2 with IC50 (8.7 and 6.4 µg/ml, respectively) relative to Dox. (21.6 and 28.3 µg/ml, respectively). The molecular docking study confirmed our ELISA result which showed the promising binding affinities of compounds 14a and 17 against Bcl2 anti-apoptotic protein. At the gene expression level, P53, BAX, DR4 and DR5 were up-regulated, while Bcl2, Il-8, and CDK4 were down-regulated in 14a, 14b and 18b treated MCF7 cells. At the protein level, compound 14b increased the activity of Caspase 8 and BAX (18.263 and 14.25 pg/ml) relative to Dox. (3.99 and 4.92 pg/ml, respectively), while the activity of Bcl2 was greatly decreased in 14a treated MCF7 (2.4 pg/ml) compared with Dox. (14.37 pg/ml). Compounds 14a and 14b caused cell cycle arrest at the G1/S phase in MCF7. Compounds 16b and 18b induced the apoptotic death of MCF7 cells. In addition, the percentage of fragmented DNA was increased significantly in 14a treated MCF7 cells.