The role of blood groups, vaccine type and gender in predicting the severity of side effects among university students receiving COVID-19 vaccines.

On March 11th, 2020, the World Health Organization (WHO) declared the coronavirus disease 2019 (COVID-19) a pandemic. To control the pandemic, billions of vaccine doses have been administered worldwide. Predictors of COVID-19 vaccine-related side effects are inconsistently described in the literature. This study aimed to identify the predictors of side effects' severity after COVID-19 vaccination among young adult students at Taif University (TU) in Saudi Arabia. An online, anonymous questionnaire was used. Descriptive statistics were calculated for numerical and categorical variables. Possible correlations with other characteristics were identified using the chi-square test. The study included 760 young adult participants from TU. Pain at the injection site (54.7%), headache (45.0%), lethargy and fatigue (43.3%), and fever (37.5%) were the most frequently reported COVID-19 vaccine-related side effects after the first dose. The most frequent side effects were reported among the 20-25-year-old age group for all doses of all vaccines. Females experienced remarkably more side effects after the second (p < 0.001) and third doses (p = 0.002). Moreover, ABO blood groups significantly correlated with vaccine-related side effects after the second dose (p = 0.020). The participants' general health status correlated with the side effects after the first and second doses (p < 0.001 and 0.022, respectively). The predictors of COVID-19 vaccine-related side effects in young, vaccinated people were blood group B, female gender, vaccine type, and poor health status.

Isolation, Characterization and Anticancer Activity of Two Bioactive Compounds from Arisaema flavum (Forssk.) Schott.

Medicinal plants play important role in the public health sector worldwide. Natural products from medicinal plants are sources of unlimited opportunities for new drug leads because of their unique chemical diversity. Researchers have focused on exploring herbal products as potential sources for the treatment of cancer, cardiac and infectious diseases. Arisaema flavum (Forssk.) is an important medicinal plant found in the northwest Himalayan regions of Pakistan. It is a poisonous plant and is used as a remedy against snake bites and scorpion stings. In this study, two bioactive compounds were isolated from Arisaema flavum (Forssk.) and their anticancer activity was evaluated against human breast cancer cell line MCF-7 using an MTT assay. The crude extract of Arisaema flavum (Forssk.) was subjected to fractionation using different organic solvents in increasing order of polarity. The fraction indicating maximum activity was then taken for isolation of bioactive compounds using various chromatographic and spectroscopic techniques such as column chromatography, thin-layer chromatography (TLC), gas chromatography−mass spectrometry (GC-MS), Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy (NMR). Crude extract of Arisaema flavum (Forssk.), as well as various fractions extracted in different solvents such as n-hexane, chloroform and ethyl acetate, were tested against human breast cancer cell line MCF-7 using an MTT assay. The crude extract exhibited significant dose-dependent anticancer activity with a maximum activity of 78.6% at 500 µg/mL concentration. Two compounds, hexadecanoic acid ethyl ester with molecular formula C18H36O7 and molar mass 284 and 5-Oxo-19 propyl-docosanoic acid methyl ester with molecular formula C26H50O3 and molecular mass 410, were isolated from chloroform fraction. These compounds were tested against the MCF-7cell line for cytotoxic activity and exhibited a significant (p < 0.00l) decrease in cell numbers for MCF-7 cells with IC50 of 25 µM after 48 h of treatment. Results indicated that Arisaema flavum (Forssk.) possesses compounds with cytotoxic activity that can further be exploited to develop anticancer formulations.

Synthesis, DFT Analyses, Antiproliferative Activity, and Molecular Docking Studies of Curcumin Analogues.

With 19.3 million new cases and almost 10 million deaths in 2020, cancer has become a leading cause of death today. Curcumin and its analogues were found to have promising anticancer activity. Inspired by curcumin's promising anticancer activity, we prepared three semi-synthetic analogues by chemically modifying the diketone function of curcumin to its pyrazole counterpart. The curcumin analogues (3a−c) were synthesized by two different methods, followed by their DFT analyses to study the HOMO/LUMO configuration to access the stability of compounds (∆E = 3.55 to 3.35 eV). The curcumin analogues (3a−c) were tested for antiproliferative activity against a total of five dozen cancer cell lines in a single (10 µM) and five dose (0.001 to 100 µM) assays. 3,5-Bis(4-hydroxy-3-methoxystyryl)-1H-pyrazole-1-yl-(phenoxy)ethanone (3b) and 3,5-bis(4-hydroxy-3-methoxystyryl)-1H-pyrazole-1-yl-(2,4-dichlorophenoxy)ethanone (3c) demonstrated the most promising antiproliferative activity against the cancer cell lines with growth inhibitions of 92.41% and 87.28%, respectively, in a high single dose of 10 µM and exhibited good antiproliferative activity (%GIs > 68%) against 54 out of 56 cancer cell lines and 54 out of 60 cell lines, respectively. The compound 3b and 3c demonstrated the most potent antiproliferative activity in a 5-dose assay with GI50 values ranging between 0.281 and 5.59 µM and 0.39 and 0.196 and 3.07 µM, respectively. The compound 3b demonstrated moderate selectivity against a leukemia panel with a selectivity ratio of 4.59. The HOMO-LUMO energy-gap (∆E) of the compounds in the order of 3a > 3b > 3c, was found to be in harmony with the anticancer activity in the order of 3c ≥ 3b > 3a. Following that, all of the curcumin analogues were molecular docked against EGFR, one of the most appealing targets for antiproliferative activity. In a molecular docking simulation, the ligand 3b exhibited three different types of interactions: H-bond, π-π-stacking and π-cationic. The ligand 3b displayed three H-bonds with the residues Met793 (with methoxy group), Lys875 (with phenolic group) and Asp855 (with methoxy group). The π-π-stacking interaction was observed between the phenyl (of phenoxy) and the residue Phe997, while π-cationic interaction was displayed between the phenyl (of curcumin) and the residue Arg841. Similarly, the ligand 3c displayed five H-bonds with the residue Met793 (with methoxy and phenolic groups), Lys845 (methoxy group), Cys797 (phenoxy oxygen), and Asp855 (phenolic group), as well as a halogen bond with residue Cys797 (chloro group). Furthermore, all the compound 3a−c demonstrated significant binding affinity (−6.003 to −7.957 kcal/mol) against the active site of EGFR. The curcumin analogues described in the current work might offer beneficial therapeutic intervention for the treatment and prevention of cancer. Future anticancer drug discovery programs can be expedited by further modifying these analogues to create new compounds with powerful anticancer potentials.

Tailoring of Rosuvastatin Calcium and Atenolol Bilayer Tablets for the Management of Hyperlipidemia Associated with Hypertension: A Preclinical Study.

Hyperlipidemia is still the leading cause of heart disease in patients with hypertension. The purpose of this study is to make rosuvastatin calcium (ROS) and atenolol (AT) bilayer tablets to treat coexisting dyslipidemia and hypertension with a single product. ROS was chosen for the immediate-release layer of the constructed tablets, whereas AT was chosen for the sustained-release layer. The solid dispersion of ROS with sorbitol (1:3 w/w) was utilized in the immediate-release layer while hydroxypropyl methylcellulose (HPMC), ethylcellulose (EC), and sodium bicarbonate were incorporated into the floating sustained-release layer. The concentrations of HPMC and EC were optimized by employing 32 full factorial designs to sustain AT release. The bilayer tablets were prepared by the direct compression method. The immediate-release layer revealed that 92.34 ± 2.27% of ROS was released within 60 min at a pH of 1.2. The second sustained-release layer of the bilayer tablets exhibited delayed release of AT (96.65 ± 3.36% within 12 h) under the same conditions. The release of ROS and AT from the prepared tablets was found to obey the non-Fickian diffusion and mixed models (zero-order, Higuchi and Korsmeyer-Peppas), respectively. Preclinical studies using rabbit models investigated the impact of ROS/AT tablets on lipid profiles and blood pressure. A high-fat diet was used to induce obesity in rabbits. Bilayer ROS/AT tablets had a remarkable effect on decreasing the lipid profiles, slowing weight gain, and lowering blood pressure to normal levels when compared to the control group.

Effectiveness of physical activity on immunity markers and quality of life in cancer patient: a systematic review.

Background: Cancer is a huge group of diseases that can affect various body parts of humans but also has a psychological, societal, and economic impact. Physical activity can improve the quality of life (QOL) and immunity, while moderate intensity exercise can reduce the probability of this lethal disease. The current study aimed to determine the effect of physical activity on immune markers and QOL in cancer patients as well as to evaluate cancer-related fatigue (CRF) and its association with physical activity. Methodology: Before starting the study, the study protocol was registered in PROSPERO (registration number CRD42021273292). An electronic literature search was performed by combining MeSH terminology and keywords used with the Boolean operators "OR" and "AND" to find relevant published studies on PubMed, Scopus, Cochrane, and ScienceDirect databases. The Joanna Briggs Institute (JBI) critical evaluation checklist was used to assess the quality of selected studies, while the GRADE approach was used to see the quality of evidence. Results: A total of 13,931 studies were retrieved after the search on databases. After the scrutiny of studies by reading the title of articles and the inclusion/exclusion criteria, a total of 54 studies were selected for further screening by reading the full texts. In the final, a total of nine studies were selected for the current systematic review and proceeded for data extraction. The patients who were doing different exercises showed improvements in immunity, QOL, and reduction in CRF. A significant reduction in tumour necrosis factor-α (TNF-α), C reactive protein (CRP), interleukin-8 (IL-8), IL-6, and an increase in natural killer (NK) cells levels was also observed. Conclusions: The exercise program is safe and beneficial to improve the quality of life and immunity markers before, during, and after cancer treatment. Physical exercise may also help patients to overcome the adverse effects of the treatment and to reduce the chance of developing new tumours in the future.

Ligand-based design, synthesis, computational insights, and in vitro studies of novel N-(5-Nitrothiazol-2-yl)-carboxamido derivatives as potent inhibitors of SARS-CoV-2 main protease.

The global outbreak of the COVID-19 pandemic provokes scientists to make a prompt development of new effective therapeutic interventions for the battle against SARS-CoV-2. A new series of N-(5-nitrothiazol-2-yl)-carboxamido derivatives were designed and synthesised based on the structural optimisation principle of the SARS-CoV Mpro co-crystallized WR1 inhibitor. Notably, compound 3b achieved the most promising anti-SARS-CoV-2 activity with an IC50 value of 174.7 µg/mL. On the other hand, compounds 3a, 3b, and 3c showed very promising SARS-CoV-2 Mpro inhibitory effects with IC50 values of 4.67, 5.12, and 11.90 µg/mL, respectively. Compound 3b docking score was very promising (-6.94 kcal/mol) and its binding mode was nearly similar to that of WR1. Besides, the molecular dynamics (MD) simulations of compound 3b showed its great stability inside the binding pocket until around 40 ns. Finally, a very promising SAR was concluded to help to design more powerful SARS-CoV-2 Mpro inhibitors shortly.

Development of Narrow-Bore C18 Column for Fast Separation of Peptides and Proteins in High-Performance Liquid Chromatography.

Separation with high efficiency and good resolution is constantly in demand in the pharmaceutical industry. The fast and efficient separation of complex samples such as peptides and proteins is a challenging task. To achieve high efficiency with good resolution, chromatographers are moving towards small particles packed into narrow-bore columns. Silica monolith particles (sub-2 µm) were derivatized with chlorodimethyl octadecyl silane (C18) and packed into stainless steel columns (100 mm × 1.8 mm i.d) by a slurry-packing method. The developed columns were used for the separation of peptides and proteins. A separation efficiency (N) of 40,000 plates/column (400,000 plates/m) was achieved for the mixture of five peptides. Similarly, the fast separation of the peptides was carried out using a high flow rate, and the separation of the five peptides was achieved in one minute with high efficiency (N ≅ 240,000 plates/m). The limit of detection (DL) and the limit of quantification (QL) for each analyte were determined by developing a linear regression curve with relatively very low concentrations of the target compound. The average values of the QL for the peptide and proteins were 0.55 ng and 0.48 ng, respectively, using short C18 column (1.8 mm × 100 mm) UV (at 214 nm). The fast analysis of peptides and proteins with such high efficiency and good resolution has not been reported in the literature yet. Owing to high efficiency, these home-made columns could be used as an alternative to the expensive commercial columns for peptide and protein separation.

Screening a Panel of Topical Ophthalmic Medications against MMP-2 and MMP-9 to Investigate Their Potential in Keratoconus Management.

Keratoconus (KC) is a serious disease that can affect people of any race or nationality, although the exact etiology and pathogenic mechanism are still unknown. In this study, thirty-two FDA-approved ophthalmic drugs were exposed to virtual screening using docking studies against both the MMP-2 and MMP-9 proteins to find the most promising inhibitors as a proposed computational mechanism to treat keratoconus. Matrix metalloproteinases (MMPs) are zinc-dependent proteases, and MMP inhibitors (MMPIs) are usually designed to interact with zinc ion in the catalytic (CAT) domain, thus interfering with enzymatic activity. In our research work, the FDA-approved ophthalmic medications will be investigated as MMPIs, to explore if they can be repurposed for KC treatment. The obtained findings of the docking study suggest that atenolol and ampicillin are able to accommodate into the active sites of MMP-2 and MMP-9. Additionally, both exhibited binding modes similar to inhibitors used as references, with an ability to bind to the zinc of the CAT. Molecular dynamic simulations and the MM-GBSA binding free-energy calculations revealed their stable binding over the course of 50 ns. An additional pharmacophoric study was carried out on MMP-9 (PDB ID: 1GKC) using the co-crystallized ligand as a reference for the future design and screening of the MMP-9 inhibitors. These promising results open the door to further biological research to confirm such theoretical results.

Biological Effect of Quercetin in Repairing Brain Damage and Cerebral Changes in Rats: Molecular Docking and In Vivo Studies.

This study examined the protective effect of quercetin against high-altitude-induced brain damage in rats. A molecular docking study was performed to investigate the potential effect of quercetin in reducing brain damages through its ability to target the oxidative stress enzymes. Biomarker assessment screening assays were also performed then followed by in vivo studies. Three groups of rats were divided into the control group, an untreated animal model group with induced brain damage, and finally, the quercetin treated group that received quercetin dose equal to 20 mg/kg of their body weights. Molecular docking studies and biomarker assessment screening assays proved the potential effect of quercetin to affect the level of representative biomarkers glutathione (GSH), glutathione reductase (GR), glutathione-S-transferase (GST), glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA). Additionally, the protective effect of quercetin against high altitude, low pressure, and low oxygen was also investigated by exploring the brain histopathology of experimental rats. Brain damage was observed in the untreated animal model group. After treatment with quercetin, the cerebral edema in the brain tissues was improved significantly, confirming the protective effects of quercetin. Therefore, quercetin can be used as a natural food additive to protect from the highaltitude-induced brain damage.

Evaluation of Bi-Lateral Co-Infections and Antibiotic Resistance Rates among COVID-19 Patients.

In addition to the pathogenesis of SARS-CoV-2, bacterial co-infection plays an essential role in the incidence and progression of SARS-CoV-2 infections by increasing the severity of infection, as well as increasing disease symptoms, death rate and antimicrobial resistance (AMR). The current study was conducted in a tertiary-care hospital in Lahore, Pakistan, among hospitalized COVID-19 patients to see the prevalence of bacterial co-infections and the AMR rates among different isolated bacteria. Clinical samples for the laboratory diagnosis were collected from 1165 hospitalized COVID-19 patients, of which 423 were found to be positive for various bacterial infections. Most of the isolated bacteria were Gram-negative rods (n = 366), followed by Gram-positive cocci (n = 57). A significant association (p < 0.05) was noted between the hospitalized COVID-19 patients and bacterial co-infections. Staphylococcus aureus (S. aureus) showed high resistance against tetracycline (61.7%), Streptococcus pyogenes against penicillin (100%), E. coli against Amp-clavulanic acid (88.72%), Klebsiella pneumoniae against ampicillin (100%), and Pseudomonas aeruginosa against ciprofloxacin (75.40%). Acinetobacter baumannii was 100% resistant to the majority of tested antibiotics. The prevalence of methicillin-resistant S. aureus (MRSA) was 14.7%. The topmost symptoms of >50% of COVID-19 patients were fever, fatigue, dyspnea and chest pain with a significant association (p < 0.05) in bacterial co-infected patients. The current study results showed a comparatively high prevalence of AMR, which may become a severe health-related issue in the future. Therefore, strict compliance of antibiotic usage and employment of antibiotic stewardship programs at every public or private institutional level are recommended.

Discovery of pyridine- sulfonamide hybrids as a new scaffold for the development of potential VEGFR-2 inhibitors and apoptosis inducers.

New sulfonamide derivatives have been synthesized and tested as antitumor agents. All newly synthesized compounds were tested in vitro against 60 lines of human cancer cells. Compound VIIb shows broad-spectrum activity with a mean inhibition value of 91.67% against all cell lines. It exhibited potent anticancer activity with GI50 values of 1.06-8.92 µM relative to most of the tested cancer cell lines. Compound VIIb has been tested for enzyme inhibition activity toward vascular endothelial growth factor receptor 2, where VEGFR-2 was potently inhibited at a lower IC50 value of 3.6 µM, compared with sorafenib (IC50 = 4.8 µM). Hybrid VIIb was also able to induce cell cycle disturbance and apoptosis in Renal UO-31 cells, as shown by DNA flow cytometry and Annexin V-FITC/PI assays. It has also revealed lower Bcl-2 protein expression anti-apoptotic levels and higher BAX, p53, and caspases 3 expression levels.

Novel piperazine-chalcone hybrids and related pyrazoline analogues targeting VEGFR-2 kinase; design, synthesis, molecular docking studies, and anticancer evaluation.

New piperazine-chalcone hybrids and related pyrazoline derivatives have been designed and synthesised as potential vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors. The National Cancer Institute (NCI) has selected six compounds to evaluate their antiproliferative activity in vitro against 60 human cancer cells lines. Preliminary screening of the examined compounds indicated promising anticancer activity against number of cell lines. The enzyme inhibitory activity against VEGFR-2 was evaluated and IC50 of the tested compounds ranged from 0.57 µM to 1.48 µM. The most potent derivatives Vd and Ve were subjected to further investigations. A cell cycle analysis showed that both compounds mainly arrest HCT-116 cell cycle in the G2/M phase. Annexin V-FITC apoptosis assay showed that Vd and Ve induced an approximately 18.7-fold and 21.2-fold total increase in apoptosis compared to the control. Additionally, molecular docking study was performed against VEGFR (PDB ID: 4ASD) using MOE 2015.10 software and Sorafenib as a reference ligand.

Development of pyridazine derivatives as potential EGFR inhibitors and apoptosis inducers: Design, synthesis, anticancer evaluation, and molecular modeling studies.

Novel hybrids of pyridazine-pyrazoline were synthesized aiming to develop new antiproliferative candidates. All compounds were submitted to the National Cancer Institute (NCI), USA, and many were proved to have significant antiproliferative activity. In addition, in vitro studies of the epidermal growth factor receptor (EGFR) inhibition showed that compounds IXn, IXg, IXb and IXl exhibited excellent inhibitory effect (IC50 = 0.65, 0.75, 0.82 and 0.84 µM, respectively) compared to Erlotinib (IC50 = 0.95 µM). The mechanistic effectiveness in cell cycle progression, apoptotic induction and gene regulation were assessed for the promising compounds IXg and IXn due to their significant EGFR inhibition. Flow cytometeric analysis indicated that compounds IXg and IXn result in increased cell numbers in phase G2/M, suggesting cell cycle arrest in phase G2/M in UO-31cells. Furthermore, real time PCR assay illustrated that compounds IXg and IXn elevated Bax/Bcl2 ratio which confirmed the mechanistic pathway of them. Moreover, the apoptotic induction of UO-31 renal cancer cells was enhanced effectively through activation of caspase-3 by compounds IXg and IXn. On the other hand, molecular docking study was performed to investigate binding mode of interaction of compounds with EGFR-PK in the active site with the aim of rationalizing its promising inhibitory activity. Finally, based on the aforementioned findings, compounds IXg and IXn could be considered as effective apoptosis modulators and promising leads for future development of new anti-renal cancer agents.

Synthesis, full chemical characterisation and development of validated methods for the quantification of (±)-4'-methylmethcathinone (mephedrone): a new "legal high".

The recent global increase in the abuse of 4'-methylmethcathinone and related compounds has developed a requirement for full chemical characterisation of these products. In this work we present full synthetic and chemical characterisation data and supplemental information for mephedrone synthesised as both the hydrobromide and hydrochloride salt. Additionally we report the first fully validated chromatographic methods for the detection and quantitative analysis of the substance both in its pure form and in the presence of a number of common adulterants used in illicit drug manufacture.