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Mohamed A Abdelgawad,1 Arafa Musa,2 Atiah H Almalki,3,4 Sami I Alzarea,5 Ehab M Mostafa,2 Mostafa M Hegazy,6 Gomaa Mostafa-Hedeab,7 Mohammed M Ghoneim,6,8 Della GT Parambi,1 Rania B Bakr,1 Nayef S Al-Muaikel,9 Abdullah S Alanazi,10,11 Metab Alharbi,12 Waqas Ahmad,13 Syed NA Bukhari,1 Mohammad M Al-Sanea1 1Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf, 72341, Saudi Arabia; 2Department of Pharmacognosy, College of Pharmacy, Jouf University, Sakaka, 72341, Saudi Arabia; 3Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, Taif, 21944, Saudi Arabia; 4Addiction and Neuroscience Research Unit, Taif University, Taif, 21944, Saudi Arabia; 5Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Aljouf, 72341, Saudi Arabia; 6Department of Pharmacognosy, Faculty of Pharmacy, Al-Azhar University, Cairo, 11371, Egypt; 7Department of Pharmacology, Medical College, Jouf University, Sakaka, Aljouf, 72341, Saudi Arabia; 8Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah, 13713, Saudi Arabia; 9Department of Chemistry, College of Science, Jouf University, Sakaka, Aljouf, 72341, Saudi Arabia; 10Department of Clinical Pharmacy, College of Pharmacy, Jouf University, Sakaka, Aljouf, Saudi Arabia; 11Health Sciences Research Unit, Jouf University, Sakaka, Aljouf, Saudi Arabia; 12Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia; 13Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, MalaysiaCorrespondence: Mohamed A AbdelgawadDepartment of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf, 72341, Kingdom of Saudi ArabiaTel +966 595435214Email mohamedabdelwahab976@yahoo.comArafa MusaDepartment of Pharmacognosy, College of Pharmacy, Jouf University, Sakaka, Aljouf, 72341, Kingdom of Saudi ArabiaTel +966 558775403Email akmusa@ju.edu.saIntroduction: Epidermal growth factor receptor (EGFR) inhibition is an imperative therapeutic approach targeting various types of cancer including colorectal, lung, breast, and pancreatic cancer types. Moreover, cyclooxygenase-2 (COX-2) is frequently overexpressed in different types of cancers and has a role in the promotion of malignancy, apoptosis inhibition, and metastasis of tumor cells. Combination therapy has been emerged to improve the therapeutic benefit against cancer and curb intrinsic and acquired resistance.Methods: Three semi-synthetic series of compounds (C1-4, P1-4, and G1-4) were prepared and evaluated biologically as potential dual epidermal growth factor receptor (EGFR) and COX-2 inhibitors. The main phenolic constituents of Amaranthus spinosus L. (p-coumaric, caffeic and gallic) acids have been isolated and subsequently subjected to diazo coupling with various amines to get novel three chemical scaffolds with potential anticancer activities.Results: Compounds C4 and G4 showed superior inhibitory activity against EGFR (IC50: 0.9 and 0.5 μM, respectively) and displayed good COX-2 inhibition (IC50: 4.35 and 2.47 μM, respectively). Moreover, the final compounds were further evaluated for their cytotoxic activity against human colon cancer (HT-29), pancreatic cancer (PaCa-2), human malignant melanoma (A375), lung cancer (H-460), and pancreatic ductal cancer (Panc-1) cell lines. Interestingly, compounds C4 and G4 exhibited the highest cytotoxic activity with average IC50 values of 1.5 μM and 2.8 μM against H-460 and Panc-1, respectively. The virtual docking study was conducted to gain proper understandings of the plausible-binding modes of target compounds within EGFR and COX-2 binding sites.Discussion: The NMR of prepared compounds showed characteristic peaks that confirmed the structure of the target compounds. The synthesized benzoxazolyl scaffold containing compounds showed inhibitory activities for both COXs and EGFR which are consistent with the virtual docking study.Keywords: kinase inhibitors, anti-inflammatory, multitarget agents, BRAF, anticancer

Hasan Ejaz,1 Mahtab Ahmad,2 Sonia Younas,3 Kashaf Junaid,1 Khalid Omer Abdalla Abosalif,1 Abualgasim Elgaili Abdalla,1 Ayman Ali Mohammed Alameen,1 Mohammed Yagoub Mohammed Elamir,1 Syed Nasir Abbas Bukhari,4 Naveed Ahmad,5 Muhammad Usman Qamar2 1Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka, Al Jouf, 72388, Saudi Arabia; 2Department of Microbiology, Faculty of Life Sciences, Government College University Faisalabad, Faisalabad, 38000, Pakistan; 3Department of Pathology, Tehsil Headquarter Hospital Kamoke, Kamoke, 50661, Pakistan; 4Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf, 72388, Saudi Arabia; 5Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka, Aljouf, 72388, Saudi ArabiaCorrespondence: Muhammad Usman QamarDepartment of Microbiology, Faculty of Life Sciences, Government College University Faisalabad, Faisalabad, 38000, PakistanEmail musmanqamar@gcuf.edu.pkBackground: The therapeutic management of carbapenem-resistant Acinetobacter baumannii (CR-AB) represents a serious challenge to the public health sector because these pathogens are resistant to a wide range of antibiotics, resulting in limited treatment options. The present study was planned to investigate the clonal spread of CR-AB in a clinical setting.Methodology: A total of 174 A. baumannii clinical isolates were collected from a tertiary care hospitals in Lahore, Pakistan. The isolates were confirmed by VITEK 2 compact system and molecular identification of recA and blaOXA-51. Antimicrobial profile and the screening of carbapenem-resistant genes were carried out using VITEK 2 system and PCR, respectively. The molecular typing of the isolates was performed according to the Pasteur scheme.Results: Of the 174 A. baumannii isolates collected, the majority were isolated from sputum samples (46.5%) and in the intensive care unit (ICU, 75%). Among these, 113/174 (64.9%) were identified as CR-AB, and 49.5% and 24.7% harbored blaOXA-23 and blaNDM-1, respectively. A total of 11 (9.7%) isolates co-harbored blaOXA-51, blaNDM-1, and blaOXA-23. Interestingly, 46.9% of the CR-AB belonged to sequence type 2 (ST2; CC1), whereas 15.9% belonged to ST1 (CC1). All of the CR-AB isolates showed extensive resistance to clinically relevant antibiotics, except colistin.Conclusion: The study concluded CR-AB ST2 clone harboring blaOXA-23 and blaNDM-1 are widely distributed in Pakistan’s clinical settings, which could result in increased mortality. Strict compliance with the National Action Plan on Antimicrobial Resistance is necessary to reduce the impacts of these strains.Keywords: Acinetobacter baumannii, blaOXA, blaNDM, MIC, MLST

Pingping Li,1 Syed Nasir Abbas Bukhari,2 Tahseen Khan,3 Renukaradhya Chitti,4 Davan B Bevoor,5 Anand R Hiremath,6 Nagaraja SreeHarsha,7 Yogendra Singh,8 Kumar Shiva Gubbiyappa9 1Department of Nephrology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou City, Henan Province 450007, People’s Republic of China; 2Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 2014, Saudi Arabia; 3School of Pharmacy, Suresh Gyan Vihar University, Jaipur, India; 4Department of Pharmacy Practice, Sri Adichaunagiri College of Pharmacy, Adichunchanagiri University, Adichunchanagiri, Mandya, India; 5Department of Pharmacy Practice, SCS College of Pharmacy, Harapanahalli, Karnataka, India; 6Department of Pharmacology, Bapuji College of Pharmacy, Davanagere, Karnataka, India; 7Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al‐Ahsa, Saudi Arabia; 8Department of Pharmaceutical Sciences, Mahatma Gandhi College of Pharmaceutical Sciences, Jaipur, India; 9School of Pharmacy, GITAM University, Hyderabad, IndiaCorrespondence: Yogendra Singh Email yogendra.singh12223@gmail.comBackground: Apigenin is known to have a broad-spectrum efficacy in oxidative stress and conditions due to inflammation, although weak absorption, fast metabolic rate and a fast elimination (systemic) limit the pharmacological efficacy of this drug. Hence, we propose the usage of highly bioavailable Apigenin-solid lipid nanoparticles (SLNPs) to recognize such limitations. The defensive function of Apigenin-SLNPs on renal damage induced by streptozotocin (STZ) in animals was studied.Materials and Methods: We initially injected the rats with 35 mg kg− 1 streptozocin intraperitoneally, and after 7 days, the rats were then injected 150 mg kg− 1 of metformin intragastrically followed by a once-daily intragastric dose of Apigenin-SLNP (25 or 50 mg kg− 1) for a continuous period of 30 days. We then measured the level of insulin and blood glucose, superoxide dismutase, catalase and malondialdehyde in the tissues of the kidney. We also observed messenger-RNA expression of Interleukin-1β, Interleukin-6 and Tumor Necrosis Factor-alpha in renal tissue through RT-PCR technique. Moreover, H&E staining and Western blotting observed the histopathological variations and protein expression of nuclear factor erythroid 2-related factor 2/heme oxygenase/Nuclear Factor-κB signaling pathway, respectively.Results: An enhancement in the expressing of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 and a suppression in the expression of Nuclear Factor-κB occurred due to Apigenin-SLNPs treatment, which was a result of the protective mechanism of Apigenin-SLNPs which is because of not only its anti-inflammatory function (by inhibition of release of inflammatory factors) but also their anti-oxidant activity (through reduction of lipid peroxidation production).Conclusion: We found that a protective effect on diabetic nephropathy was shown due to Apigenin-SLNPs, in rats induced with streptozocin maybe through the pathway of nuclear factor erythroid 2-related factor 2/heme oxygenase-1/Nuclear Factor-κB.Keywords: Apigenin-SLNPs, DN, Nrf2, HO-1, NF-κB

Li P, Bukhari SNA, Khan T, et al. Int J Nanomedicine. 2020;15:9115–9124. The Editor and Publisher of International Journal of Nanomedicine wish to retract the published article. Concerns were raised regarding the alleged duplication of H&E images in Figure 4. Specifically, Figure 4A, Control, appears to have been duplicated with the same image for Figure 4E, Apigenin-SLNPs (50). In addition, images from Figure 4 also appear to have been duplicated with similar images from Figure 7 in Arellano-Buendia et al (2014), Oxidative Medicine and Cellular Longevity (https://doi.org/10.1155/2014/961326). Specifically, Images for Figure 4A, Control and Figure 4E, Apigenin-SLNPs (50) appear to have been duplicated with a similar image for Figure 7a and 7c from Arellano-Buendia et al (2014). The image for Figure 4C, Metformin, appears to have been duplicated with a similar image for Figure 7f from Arellano-Buendia et al (2014). The image for Figure 4D, Apigenin-SLNPs (25) appears to have been duplicated with a similar image for Figure 7d from Arellano-Buendia et al (2014). The authors did respond to our queries but were unable to provide a satisfactory explanation for the duplicated images and the Editor requested for the article to be retracted. Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Abdulsalam AM Alkhaldi,1 Harry P de Koning,2 Syed Nasir Abbas Bukhari31Biology Department, College of Science, Jouf University, Sakaka, Aljouf 2014, Saudi Arabia; 2Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK; 3Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 2014, Saudi ArabiaBackground: Human African Trypanosomiasis (HAT) and leishmaniasis are two of the most neglected challenging tropical diseases, caused by the kinetoplastid parasites Trypanosoma and Leishmania species, respectively. For both of these complex disease spectra, treatment options are limited and threatened by drug resistance, justifying urgent new drug discovery efforts.Purpose: In the present study we investigated the antitrypanosomal and antileishmanial activity of a series of 21 symmetrical α,β-unsaturated carbonyl-based compounds, each featuring two 3-methoxybenzene attached to a central cyclohexanone, tetrahydro-4-pyranone scaffold or 4-piperidone ring. Structure-activity relationships were explored with respect to substitution on positions 3, 4 and 6 of the terminal 3-methoxybenzyl groups, and seven types of central ring.Results: Compounds 3a, 3o, 3s and 3t, showed broad anti-kinetoplastid activity against all species and strains tested.Conclusion: Compound 3o featuring N-methyl-4-piperidone was found to be the most potent analog and therefore can serve as a potential lead for the development of new drug candidates for trypanosomiasis and leishmaniasis.Keywords: protozoan parasites, sleeping sickness, -α,β-unsaturated carbonyl-based compounds, cyclohexanone, piperidine

Laiba Arshad,1 Ibrahim Jantan,2 Syed Nasir Abbas Bukhari31Department of Pharmacy, Forman Christian College (A Chartered University), Lahore, Pakistan; 2School of Pharmacy, Faculty of Health and Medical Sciences, Taylor’s University, Subang Jaya, Selangor, Malaysia; 3Department of Pharmaceutical Chemistry, College of Pharmacy, Al Jouf University, Aljouf, Sakaka, Saudi ArabiaBackground: 3,5-Bis[4-(diethoxymethyl)benzylidene]-1-methyl-piperidin-4-one (BBP), a novel synthetic curcumin analogue has been revealed to possess strong in vitro and in vivo immunosuppressive effects.Purpose: The aim of present study was to prepare and characterize BBP-encapsulated polylactic-co-glycolic acid-block-polyethylene glycol (PLGA-b-PEG) nanoparticles and to evaluate its in vivo efficacy against innate and adaptive immune responses.Methods: Male BALB/c mice were orally administered with BBP alone and BBP- encapsulated nanoparticles equivalent to 5, 10 and 20 mg/kg of BBP in distilled water for a period of 14 days. The immunomodulatory potential was appraised by determining its effects on non-specific and specific immune parameters.Results: The results showed that BBP was successfully encapsulated in PLGA-b-PEG polymer with 154.3 nm size and high encapsulation efficiency (79%) while providing a sustained release for 48 hours. BBP nanoparticles showed significant enhanced dose-dependent reduction on the migration of neutrophils, Mac-1 expression, phagocytic activity, reactive oxygen species (ROS) production, serum levels of ceruloplasmin and lysozyme, immunoglobulins and myloperoxidase (MPO) plasma levels when compared to unencapsulated BBP. Enhanced dose-dependent inhibition was also observed on lymphocyte proliferation along with the downregulation of effector cells expression and release of cytokines, and reduction in rat paw oedema in BBP nanoparticles treated mice. At higher doses the suppressive effects of the BBP nanoparticles on various cellular and humoral parameters of immune responses were comparable to that of cyclosporine-A at 20 mg/kg.Conclusion: These findings suggest that the immunosuppressive effects of BBP were enhanced as PLGA-b-PEG nanoparticles.Keywords: αβ-unsaturated carbonyl-based compound, curcumin analogue, PLGA-b-PEG nanoparticles, immunosuppression, innate immune response, humoral immune response

Menaga Ilangkovan, Ibrahim Jantan, Mohamed Ahmed Mesaik, Syed Nasir Abbas BukhariDrug and Herbal Research Center, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, MalaysiaAbstract: Phyllanthus amarus (family: Euphorbiaceae) is of immense interest due to its wide spectrum of biological activities. In the present study, the standardized 80% ethanol extract of P. amarus was investigated for its modulatory activity on various cellular immune parameters, including chemotaxis of neutrophils, engulfment of Escherichia coli by neutrophils, and Mac-1 expression, in leukocytes isolated from treated/nontreated Wistar-Kyoto rats. The detailed cell-mediated activity of P. amarus was also investigated, including analysis of the effects on T- and B-cell proliferation and CD4+ and CD8+ T-cell subsets in splenic mononuclear cells, and estimation of serum cytokine production by activated T-cells. The main components of the extract, phyllanthin, hypophyllanthin, corilagin, geraniin, ellagic acid, and gallic acid were identified and quantitatively analyzed in the extracts, using validated reversed-phase high-performance liquid chromatography (HPLC) methods. N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced neutrophils isolated from rats administered with the extract of P. amarus, at doses ranging from 100 to 400 mg/kg for 14 days, revealed a significant dose-dependent reduction in neutrophil migration (P

Jian Sian Lee, Syed Nasir Abbas Bukhari, Norsyahida Mohd Fauzi Drug and Herbal Research Center, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia Abstract: The immune system is the defense mechanism in living organisms that protects against the invasion of foreign materials, microorganisms, and pathogens. It involves multiple organs and tissues in human body, such as lymph nodes, spleen, and mucosa-associated lymphoid tissues. However, the execution of immune activities depends on a number of specific cell types, such as B cells, T cells, macrophages, and granulocytes, which provide various immune responses against pathogens. In addition to normal physiological functions, abnormal proliferation, migration, and differentiation of these cells (in response to various chemical stimuli produced by invading pathogens) have been associated with several pathological disorders. The unwanted conditions related to these cells have made them prominent targets in the development of new therapeutic interventions against various pathological implications, such as atherosclerosis and autoimmune diseases. Chalcone derivatives exhibit a broad spectrum of pharmacological activities, such as immunomodulation, as well as anti-inflammatory, anticancer, antiviral, and antimicrobial properties. Many studies have been conducted to determine their inhibitory or stimulatory activities in immune cells, and the findings are of significance to provide a new direction for subsequent research. This review highlights the effects of chalcone derivatives in different types of immune cells. Keywords: macrophages, neutrophils, T-cells

Ibrahim Jantan,1,* Syed Nasir Abbas Bukhari,1,* Olayiwola A Adekoya,2 Ingebrigt Sylte3 1Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia; 2Department of Pharmacy, Faculty of Health Science, UiT The Arctic University of Norway, Tromsø, Norway; 3Department of Medical Biology, Faculty of Health Science, UiT The Arctic University of Norway, Tromsø, Norway *These authors contributed equally to this work Abstract: Arachidonic acid metabolism leads to the generation of key lipid mediators which play a fundamental role during inflammation. The inhibition of enzymes involved in arachidonic acid metabolism has been considered as a synergistic anti-inflammatory effect with enhanced spectrum of activity. A series of 1,3-diphenyl-2-propen-1-one derivatives were investigated for anti-inflammatory related activities involving inhibition of secretory phospholipase A2, cyclooxygenases, soybean lipoxygenase, and lipopolysaccharides-induced secretion of interleukin-6 and tumor necrosis factor-alpha in mouse RAW264.7 macrophages. The results from the above mentioned assays exhibited that the synthesized compounds were effective inhibitors of pro-inflammatory enzymes and cytokines. The results also revealed that the chalcone derivatives with 4-methlyamino ethanol substitution seem to be significant for inhibition of enzymes and cytokines. Molecular docking experiments were carried out to elucidate the molecular aspects of the observed inhibitory activities of the investigated compounds. Present findings increase the possibility that these chalcone derivatives might serve as a beneficial starting point for the design and development of improved anti-inflammatory agents. Keywords: anti-inflammatory, tumor necrosis factor-alpha, lipopolysaccharides, molecular docking