Eldeeb, M. A., M. Esmaili, M. Hassan, and M. A. Ragheb, "The Role of PTEN-L in Modulating PINK1-Parkin-Mediated Mitophagy", Neurotoxicity Research, vol. 40, issue 4, pp. 1103 - 1114, 2022. AbstractWebsite

An inherent challenge that mitochondria face is the continuous exposure to diverse stresses which increase their likelihood of dysregulation. In response, human cells have evolved sophisticated quality control mechanisms to identify and eliminate abnormal dysfunctional mitochondria. One pivotal mitochondrial quality control pathway is PINK1/Parkin-dependent mitophagy which mediates the selective removal of the dysfunctional mitochondria from the cell by autophagy. PTEN-induced putative kinase 1 (PINK1) is a mitochondrial Ser/Thr kinase that was originally identified as a gene responsible for autosomal recessive early-onset Parkinson’s disease (PD). Notably, upon failure of mitochondrial import, Parkin, another autosomal-recessive PD gene, is recruited to mitochondria and mediates the autophagic clearance of deregulated mitochondria. Importantly, recruitment of Parkin to damaged mitochondria hinges on the accumulation of PINK1 on the outer mitochondrial membrane (OMM). Normally, PINK1 is imported from the cytosol through the translocase of the outer membrane (TOM) complex, a large multimeric channel responsible for the import of most mitochondrial proteins. After import, PINK1 is rapidly degraded. Thus, at steady-state, PINK1 levels are kept low. However, upon mitochondrial import failure, PINK1 accumulates and forms a high-molecular weight > 700 kDa complex with TOM on the OMM. Thus, PINK1 functions as sensor, tagging dysfunctional mitochondria for Parkin-mediated mitophagy. Although much has been learned about the function of PINK1 in mitophagy, the biochemical and structural basis of negative regulation of PINK1 operation and functions is far from clear. Recent work unveiled new players as PTEN-l as negative regulator of PINK1 function. Herein, we review key aspects of mitophagy and PINK1/Parkin-mediated mitophagy with highlighting the role of negative regulation of PINK1 function and presenting some of the key future directions in PD cell biology.

Eldeeb, M. A., M. A. Ragheb, M. H. Soliman, and R. P. Fahlman, "Regulation of Neurodegeneration-associated Protein Fragments by the N-degron Pathways", Neurotoxicity Research, vol. 40, issue 1, pp. 298 - 318, 2022. AbstractWebsite

Among the most salient features that underpin the development of aging-related neurodegenerative disorders are the accumulation of protein aggregates and the decrease in cellular degradation capacity. Mammalian cells have evolved sophisticated quality control mechanisms to repair or eliminate the otherwise abnormal or misfolded proteins. Chaperones identify unstable or abnormal conformations in proteins and often help them regain their correct conformation. However, if repair is not an option, abnormal proteins are selectively degraded to prevent undesired interactions with other proteins or oligomerization into toxic multimeric complexes. The autophagic-lysosomal system and the ubiquitin–proteasome system mediate the selective and targeted degradation of abnormal or aberrant protein fragments. Despite an increasing understanding regarding the molecular responses that counteract the formation and clearance of dysfunctional protein aggregates, the role of N-degrons in these processes is poorly understood. Previous work demonstrated that the Arg-N-end rule degradation pathway (Arg-N-degron pathway) mediates the degradation of neurodegeneration-associated proteins, thereby regulating crucial signaling hubs that modulate the progression of neurodegenerative diseases. Herein, we discuss the functional interconnection between N-degron pathways and proteins associated with neurodegenerative disorders, including Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease. We also highlight some future prospects related to how the molecular insights gained from these processes will help unveil novel therapeutic approaches.

Ragab, M. S., M. H. Soliman, M. R. Shehata, M. M. Shoukry, and M. A. Ragheb, "Design, synthesis, spectral characterization, photo-cleavage, and in vitro evaluation of anticancer activities of new transition metal complexes of piperazine based Schiff base-oxime ligand", Applied Organometallic Chemistry, vol. 36, issue 9: John Wiley & Sons, Ltd, pp. e6802, 2022. AbstractWebsite

The newly synthesized Schiff base-oxime ligand, namely, (2Z,3E)-3-((3-(4-(3-(((2E,3E)-3-(hydroxyimino)butan-2-ylidene)amino)propyl)piperazin-1-yl)propyl)imino)butan-2-one oxime (H2L) and its Co (II), Cu (II), and Zn (II) complexes were reported. The characterization was accomplished with the aid of CHN-EA, mass, fourier transform infrared spectroscopy (FT-IR), electronic spectra, magnetic moment, molar conductance and TGA. According to the spectroscopic approaches, the synthesized ligand (H2L) may act as a tetradentate or hexadentate (bis-tridentate) coordinating ligand through the azomethine nitrogen, piperazinyl nitrogens, and oximato-nitrogens affording distorted square planar mononuclear Co (II) complex or tetrahedrally distorted square planar binuclear Cu (II) and Zn (II) complexes whereas the coordination mode varies according to the nature of the metal ion. The microbial resistance of all the synthesized compounds was evaluated and reported. Findings showed that the Cu (II) complex has mostly the highest inhibitory effects against all tested microbial strains. Besides, the anticancer nature of the studied compounds was also evaluated against a panel of three different human cancer cells, including (HCT-116), (MDA-MB-231), (HepG2) in addition to the (WI-38) used as a healthy cells. In general, the Cu (II) complex displayed the best cytotoxic profiles against the tested cells than the Co (II) and Zn (II) complexes with negligible toxicity towards the (WI-38) normal cells. The DNA cleavage activities of all tested compounds were assayed against pBR322 plasmid DNA. Whereas, the Cu (II) complex showed the highest DNA cleavage propensity, which proceeds predominantly via the oxidative mechanism. Additionally, flow cytometric analysis dictates that the Cu (II) complex induces cell cycle arrest in S-phase and apoptotic cell death on HCT-116 cells. The morphological transformations distinguished in HCT-116 cells treated with Cu (II) complex have been depicted with the aid of scanning electron microscopy (SEM). The docking results indicate that the Cu (II) complex strongly interacts with human colon cancer (6GUE), Escherichia coli (3T88), Klebsiella pneumoniae (4HL2), and Staphylococcus aureus (3WQU) proteins, through different modes of interactions that harmonize successfully with the experimental results.

Ragheb, M. A., H. E. Abdelrashid, E. M. Elzayat, I. A. Abdelhamid, and M. H. Soliman, "Novel cyanochalcones as potential anticancer agents: apoptosis, cell cycle arrest, DNA binding, and molecular docking studies", Journal of Biomolecular Structure and Dynamics: Taylor & Francis, pp. 1-19, 2024. Abstract
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Ragheb, M. A., F. G. Mohamed, H. M. Diab, M. S. Ragab, M. Emara, A. H. M. Elwahy, I. A. Abdelhamid, and M. H. Soliman, "Novel Bis (2‐cyanoacrylamide) Linked to Sulphamethoxazole: Synthesis, DNA Interaction, Anticancer, ADMET, Molecular Docking, and DFT Studies", Chemistry & Biodiversity, vol. 21, issue 4, pp. e202301341, 2024. Abstract
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Ragheb, M. A., M. H. Soliman, I. A. Abdelhamid, M. M. Shoukry, M. Haukka, and M. S. Ragab, "Anticancer behaviour of 2, 2′-(pyridin-2-ylmethylene) bis (5, 5-dimethylcyclohexane-1, 3-dione)-based palladium (II) complex and its DNA, BSA binding propensity and DFT study", Journal of Inorganic Biochemistry, vol. 253: Elsevier, pp. 112488, 2024. Abstract
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Ragheb, M. A., R. E. Abdelwahab, A. F. Darweesh, M. H. Soliman, A. H. M. Elwahy, and I. A. Abdelhamid, "Hantzsch‐Like Synthesis, DNA Photocleavage, DNA/BSA Binding, and Molecular Docking Studies of Bis (sulfanediyl) bis (tetrahydro‐5‐deazaflavin) Analogs Linked to Naphthalene Core", Chemistry & Biodiversity, vol. 19, issue 9, pp. e202100958, 2022. Abstract
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Ragheb, M. A., R. S. Omar, M. H. Soliman, A. H. M. Elwahy, and I. A. Abdelhamid, "Synthesis, characterization, DNA photocleavage, in silico and in vitro DNA/BSA binding properties of novel hexahydroquinolines", Journal of Molecular Structure, vol. 1267: Elsevier, pp. 133628, 2022. Abstract
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Soliman, M. H., M. A. Ragheb, E. M. Elzayat, M. S. Mohamed, N. El-Ekiaby, A. I. Abdelaziz, and A. - H. A. Abdel-Wahab, "MicroRNA-372-3p predicts response of TACE patients treated with doxorubicin and enhances chemosensitivity in hepatocellular carcinoma", Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents), vol. 21, issue 2: Bentham Science Publishers, pp. 246-253, 2021. Abstract
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Ragheb, M. A., M. H. Soliman, E. M. Elzayat, M. S. Mohamed, N. El-Ekiaby, A. I. Abdelaziz, and A. - H. A. Abdel-Wahab, "MicroRNA-520c-3p Modulates Doxorubicin-Chemosensitivity in HepG2 Cells", Anti-cancer agents in medicinal chemistry, vol. 21, issue 2, pp. 237-245, 2021. Abstract
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