Ahmed Majeed Al-Shammari

Bio: Ahmed Majeed Al-Shammari is an academic researcher from Al-Mustansiriya University. The author has contributed to research in topics: Cancer cell & Apoptosis. The author has an hindex of 14, co-authored 66 publications receiving 599 citations. Previous affiliations of Ahmed Majeed Al-Shammari include Oregon Health & Science University & University of Alabama.

Characterization of a Novel Human-Specific STING Agonist that Elicits Antiviral Activity Against Emerging Alphaviruses

Abstract: Pharmacologic stimulation of innate immune processes represents an attractive strategy to achieve multiple therapeutic outcomes including inhibition of virus replication, boosting antitumor immunity, and enhancing vaccine immunogenicity. In light of this we sought to identify small molecules capable of activating the type I interferon (IFN) response by way of the transcription factor IFN regulatory factor 3 (IRF3). A high throughput in vitro screen yielded 4-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (referred to herein as G10), which was found to trigger IRF3/IFN-associated transcription in human fibroblasts. Further examination of the cellular response to this molecule revealed expression of multiple IRF3-dependent antiviral effector genes as well as type I and III IFN subtypes. This led to the establishment of a cellular state that prevented replication of emerging Alphavirus species including Chikungunya virus, Venezuelan Equine Encephalitis virus, and Sindbis virus. To define cellular proteins essential to elicitation of the antiviral activity by the compound we employed a reverse genetics approach that utilized genome editing via CRISPR/Cas9 technology. This allowed the identification of IRF3, the IRF3-activating adaptor molecule STING, and the IFN-associated transcription factor STAT1 as required for observed gene induction and antiviral effects. Biochemical analysis indicates that G10 does not bind to STING directly, however. Thus the compound may represent the first synthetic small molecule characterized as an indirect activator of human STING-dependent phenotypes. In vivo stimulation of STING-dependent activity by an unrelated small molecule in a mouse model of Chikungunya virus infection blocked viremia demonstrating that pharmacologic activation of this signaling pathway may represent a feasible strategy for combating emerging Alphaviruses.

Newcastle disease virus suppress glycolysis pathway and induce breast cancer cells death.

Abstract: Newcastle disease virus (NDV) can modulate cancer cell signaling pathway and induce apoptosis in cancer cells Cancer cells increase their glycolysis rates to meet the energy demands for their survival and generate ATP as the primary energy source for cell growth and proliferation Interfering the glycolysis pathway may be a valuable antitumor strategy This study aimed to assess the effect of NDV on the glycolysis pathway in infected breast cancer cells Oncolytic NDV attenuated AMHA1 strain was used in this study AMJ13 and MCF7 breast cancer cell lines and a normal embryonic REF cell line were infected with NDV with different multiplicity of infections (moi) to determine the IC50 of NDV through MTT assay Crystal violet staining was done to study the morphological changes NDV apoptosis induction was assessed using AO/PI assay NDV interference with the glycolysis pathway was examined through measuring hexokinase (HK) activity, pyruvate, and ATP concentrations, and pH levels in NDV infected and non-infected breast cancer cells and in normal embryonic cells The results showed that NDV replicates efficiently in cancer cells and spare normal cells and induce morphological changes and apoptosis in breast cancer cells but not in normal cells NDV infected cancer cells showed decreased in the HK activity, pyruvate and ATP concentrations, and acidity, which reflect a significant decrease in the glycolysis activity of the NDV infected tumor cells No effects on the normal cells were observed In conclusion, oncolytic NDV ability to reduce glycolysis pathway activity in cancer cells can be an exciting module to improve antitumor therapeutics

Linalool-Loaded Glutathione-Modified Gold Nanoparticles Conjugated with CALNN Peptide as Apoptosis Inducer and NF-κB Translocation Inhibitor in SKOV-3 Cell Line.

Abstract: Background Linalool is a monoterpene compound with various potential therapeutic applications in several medical fields. Previous studies have indicated the activity of linalool against cell lines; however, its high level of toxicity restricts its use. The aim of this study was to design and manufacture compounds with a novel structure that can be used for loading linalool, to reduce its toxicity and improve its reachable ability. Methods We synthesized and characterized a new molecule for loading linalool onto gold nanoparticles (GNPs) capped with glutathione and conjugated with a CALNN peptide. Linalool was loaded onto the GNPs via the reaction of the surface groups of both linalool and the GNPs. Moreover, the target peptide could be loaded onto the surface of the GNPs via a chemical reaction. The cytotoxic effects of linalool-GNP (LG) and linalool-GNP-CALNN peptide (LGC) conjugates against ovarian cancer cells were investigated, as were the possible mechanisms underlying the induction of apoptosis. Results Our findings illustrated the significant antiproliferative effect of LG and LGC on SKOV-3 cells. The cytotoxicity assay demonstrated that LG and LGC were selectively toxic in cancer cells and induced apoptosis by activating caspase-8, the p53 protein, and various proteins involved in apoptosis. The present data demonstrated that LG and LGC have a high therapeutic potential and should be given particular consideration as anticancer drug-delivery systems, as LG and LGC were remarkably more cytotoxic against a cancer cell line than were linalool and GNPs alone. Conclusion We concluded that LG and LGC are promising compounds that can be used for treating ovarian cancer (SKOV-3) cells via the induction of apoptosis through extrinsic and intrinsic pathways.

Fe3O4 Nanoparticles Capped with PEG Induce Apoptosis in Breast Cancer AMJ13 Cells Via Mitochondrial Damage and Reduction of NF-κB Translocation

Abstract: In the current study, polyethylene glycol (PEG) was employed to cap super magnetite nanoparticles (Fe3O4 NPs) through hydrothermal preparation. The main goal of this study is to investigate the influence of physical incorporation of polyethylene glycol (PEG) loaded Fe3O4. The anticancer potentials of these particles were studied against breast cancer cell line (AMJ13). Syntheses bare Fe3O4, and Fe3O4-PEG were confirmed by TEM, SEM, and FTIR. The size of Fe3O4 nanoparticles range of 9–20 and 5–12 nm for the Fe3O4–PEG nanoparticles which exerted superparamagnetic properties as well as elevated saturation level of magnetization at ambient conditions. The MTT test was employed to detect the ability of the bare Fe3O4 and Fe3O4-PEG on the proliferative of AMJ13 cells. IC50 values was 37.33 µg mL− 1 for bare Fe3O4 and 18.23 µg mL−1 for Fe3O4-PEG. AMJ13 Cells exposed to bare Fe3O4, and Fe3O4-PEG NPs demonstrated a significant cell death, which increased with PEG, loaded Fe3O4 NPs. The capability of Fe3O4-PEG to induce cellular apoptosis was tested using DAPI, Acridine orange/ Ethedium bromide stains, flow cytometry, with the assays of mitochondrial membrane potential (MMP), and the production of reactive oxygen species (ROS). RT-PCR, and immunofluorescence were performed to measure expression levels of Bax and Bcl-2 proteins. The toxicity of bare Fe3O4 and Fe3O4-PEG nanoparticles using animal model were investigated. Animal’s body weight, liver and kidney function enzymes, and histological alterations for liver, kidney, and lungs were addressed. The findings demonstrated that nanoparticles were biocompatible with liver and kidney function enzymes and no significant alterations were recorded in the liver, kidney and the lungs. Both nanoparticles revealed a proliferation inhibitory effect on AMJ13 cells, resulting in apoptosis as a novel pathway that involve the mitochondrial damage and NF-kB. Taken together the present data suggest that bare Fe3O4 and Fe3O4-PEG could be promising therapy protocol for cancer cells.

Myeloid immunosuppression and immune checkpoints in the tumor microenvironment

Abstract: Tumor-promoting inflammation and the avoidance of immune destruction are hallmarks of cancer. While innate immune cells, such as neutrophils, monocytes, and macrophages, are critical mediators for sterile and nonsterile inflammation, persistent inflammation, such as that which occurs in cancer, is known to disturb normal myelopoiesis. This disturbance leads to the generation of immunosuppressive myeloid cells, such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Due to their potent suppressive activities against effector lymphocytes and their abundance in the tumor microenvironment, immunosuppressive myeloid cells act as a major barrier to cancer immunotherapy. Indeed, various therapeutic approaches directed toward immunosuppressive myeloid cells are actively being tested in preclinical and clinical studies. These include anti-inflammatory agents, therapeutic blockade of the mobilization and survival of myeloid cells, and immunostimulatory adjuvants. More recently, immune checkpoint molecules expressed on tumor-infiltrating myeloid cells have emerged as potential therapeutic targets to redirect these cells to eliminate tumor cells. In this review, we discuss the complex crosstalk between cancer-related inflammation and immunosuppressive myeloid cells and possible therapeutic strategies to harness antitumor immune responses.

2-Deoxy-d-Glucose and Its Analogs: From Diagnostic to Therapeutic Agents.

Abstract: The ability of 2-deoxy-d-glucose (2-DG) to interfere with d-glucose metabolism demonstrates that nutrient and energy deprivation is an efficient tool to suppress cancer cell growth and survival. Acting as a d-glucose mimic, 2-DG inhibits glycolysis due to formation and intracellular accumulation of 2-deoxy-d-glucose-6-phosphate (2-DG6P), inhibiting the function of hexokinase and glucose-6-phosphate isomerase, and inducing cell death. In addition to glycolysis inhibition, other molecular processes are also affected by 2-DG. Attempts to improve 2-DG’s drug-like properties, its role as a potential adjuvant for other chemotherapeutics, and novel 2-DG analogs as promising new anticancer agents are discussed in this review.