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4 results on '"Ahmad Bin Salam"'

1. A Novel CD206 Targeting Peptide Inhibits Bleomycin-Induced Pulmonary Fibrosis in Mice

Author

Anghesom Ghebremedhin, Ahmad Bin Salam, Benjamin Adu-Addai, Steve Noonan, Richard Stratton, Md Shakir Uddin Ahmed, Chandra Khantwal, George R. Martin, Huixian Lin, Chris Andrews, Balasubramanyam Karanam, Udo Rudloff, Henry Lopez, Jesse Jaynes, and Clayton Yates

Subjects
macrophages, myofibroblasts, IPF, immunotherapy, CD206, Cytology, QH573-671
Abstract

Activated M2-polarized macrophages are drivers of pulmonary fibrosis in several clinical scenarios, including Idiopathic Pulmonary Fibrosis (IPF). In this study, we investigated the effects of targeting the CD206 receptor in M2-like macrophages with a novel synthetic analogue of a naturally occurring Host Defense Peptide (HDP), RP-832c, to decrease profibrotic cytokines. RP-832c selectively binds to CD206 on M2-polarized bone marrow-derived macrophages (BMDM) in vitro, resulting in a time-dependent decrease in CD206 expression and a transient increase in M1-macrophage marker TNF-α. To elucidate the antifibrotic effects of RP-832c, we used a murine model of bleomycin (BLM)-induced early-stage pulmonary fibrosis. RP-832c significantly reduced fibrosis in a dose-dependent manner, and decreased CD206, TGF-β1, and α-SMA expression in mouse lungs. Similarly, in an established model of lung fibrosis, RP-832c significantly decreased lung fibrosis and significantly decreased inflammatory cytokines TNF-α, IL-6, IL-10, IFN-γ, CXCL1/2, and fibrosis markers TGF-β1 and MMP-13. In comparison with the FDA-approved drugs Nintedanib and Pirfenidone, RP-832c exhibited a similar reduction in fibrosis compared to Pirfenidone, and to a greater extent than Nintedanib, with no apparent toxicities observed. In summary, our findings showed that inhibiting the profibrotic alternatively activated M2-like macrophages using a novel peptide, RP-832c, could reduce BLM-induced pulmonary fibrosis in mice, warranting the therapeutic potential of this peptide for patients with pulmonary fibrosis.

Published
2023
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2. Chirality and asymmetry increase the potency of candidate ADRM1/RPN13 inhibitors.

Author

Ravi K Anchoori, Logan George, Ssu-Hsueh Tseng, Brandon Lam, Srinidhi Polkampally, Anjali D Amiano, Palmer Foran, Hannah Tsingine, Harideep Samanapally, Fernanda Carrizo Velasquez, Samarjit Das, Deyin Xing, Ahmad Bin Salam, Balasubramanyam Karanam, Chien-Fu Hung, and Richard B S Roden

Subjects
Medicine, Science
Abstract

Bortezomib and the other licensed 20S proteasome inhibitors show robust activity against liquid tumors like multiple myeloma, but have disappointed against solid tumors including ovarian cancer. Consequently, interest is mounting in alternative non-peptide based drugs targeting the proteasome's 19S regulatory particle subunit, including its ubiquitin receptor RPN13. RA183 and RA375 are more potent analogs of the prototypic inhibitor of RPN13 (iRPN13) called RA190, and they show promise for the treatment of ovarian cancer. Here we demonstrate that rendering these candidate RPN13 inhibitors chiral and asymmetric through the addition of a single methyl to the core piperidone moiety increases their potency against cancer cell lines, with the S-isomer being more active than the R-isomer. The enhanced cancer cell cytotoxicities of these compounds are associated with improved binding to RPN13 in cell lysates, ATP depletion by inhibition of glycolysis and mitochondrial electron chain transport, mitochondrial depolarization and perinuclear clustering, oxidative stress and glutathione depletion, and rapid accumulation of high molecular weight polyubiquitinated proteins with a consequent unresolved ubiquitin proteasome system (UPS) stress response. Cytotoxicity was associated with an early biomarker of apoptosis, increased surface annexin V binding. As for cisplatin, BRCA2 and ATM deficiency conferred increased sensitivity to these iRPN13s. Ubiquitination plays an important role in coordinating DNA damage repair and the iRPN13s may compromise this process by depletion of monomeric ubiquitin following its sequestration in high molecular weight polyubiquitinated protein aggregates. Indeed, a synergistic cytotoxic response was evident upon treatment of several ovarian cancer cell lines with either cisplatin or doxorubicin and our new candidate iRPN13s, suggesting that such a combination approach warrants further exploration for the treatment of ovarian cancer.

Published
2021
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3. Chirality and asymmetry increase the potency of candidate ADRM1/RPN13 inhibitors

Author

Ssu-Hsueh Tseng, Ahmad Bin Salam, Anjali D. Amiano, Fernanda Carrizo Velasquez, Hannah Tsingine, Brandon Lam, Srinidhi Polkampally, Chien Fu Hung, Balasubramanyam Karanam, Deyin Xing, Samarjit Das, Harideep Samanapally, Palmer Foran, Ravi K. Anchoori, Logan George, and Richard B.S. Roden

Subjects
Luminescence, Cancer Treatment, Apoptosis, ADRM1, Mitochondrion, Biochemistry, Mice, Ubiquitin, Annexin, Medicine and Health Sciences, Energy-Producing Organelles, Ovarian Neoplasms, Multidisciplinary, biology, Cell Death, Chemistry, Bortezomib, Physics, Electromagnetic Radiation, Intracellular Signaling Peptides and Proteins, Animal Models, Ovarian Cancer, Mitochondria, Enzymes, Oncology, Experimental Organism Systems, Cell Processes, Physical Sciences, Medicine, Female, Cellular Structures and Organelles, Bioluminescence, Oxidoreductases, Luciferase, medicine.drug, Research Article, Science, Mice, Nude, Mouse Models, Antineoplastic Agents, Bioenergetics, Research and Analysis Methods, Benzylidene Compounds, Model Organisms, Cell Line, Tumor, medicine, Animals, Humans, Cell Proliferation, Cisplatin, Ubiquitination, Cancers and Neoplasms, Biology and Life Sciences, Proteins, Protein Complexes, Proteasomes, Cell Biology, Mice, Inbred C57BL, Proteasome, Cancer cell, Cancer research, biology.protein, Animal Studies, Enzymology, Gynecological Tumors
Abstract

Bortezomib and the other licensed 20S proteasome inhibitors show robust activity against liquid tumors like multiple myeloma, but have disappointed against solid tumors including ovarian cancer. Consequently, interest is mounting in alternative non-peptide based drugs targeting the proteasome’s 19S regulatory particle subunit, including its ubiquitin receptor RPN13. RA183 and RA375 are more potent analogs of the prototypic inhibitor of RPN13 (iRPN13) called RA190, and they show promise for the treatment of ovarian cancer. Here we demonstrate that rendering these candidate RPN13 inhibitors chiral and asymmetric through the addition of a single methyl to the core piperidone moiety increases their potency against cancer cell lines, with the S-isomer being more active than the R-isomer. The enhanced cancer cell cytotoxicities of these compounds are associated with improved binding to RPN13 in cell lysates, ATP depletion by inhibition of glycolysis and mitochondrial electron chain transport, mitochondrial depolarization and perinuclear clustering, oxidative stress and glutathione depletion, and rapid accumulation of high molecular weight polyubiquitinated proteins with a consequent unresolved ubiquitin proteasome system (UPS) stress response. Cytotoxicity was associated with an early biomarker of apoptosis, increased surface annexin V binding. As for cisplatin, BRCA2 and ATM deficiency conferred increased sensitivity to these iRPN13s. Ubiquitination plays an important role in coordinating DNA damage repair and the iRPN13s may compromise this process by depletion of monomeric ubiquitin following its sequestration in high molecular weight polyubiquitinated protein aggregates. Indeed, a synergistic cytotoxic response was evident upon treatment of several ovarian cancer cell lines with either cisplatin or doxorubicin and our new candidate iRPN13s, suggesting that such a combination approach warrants further exploration for the treatment of ovarian cancer.

Published
2021

4. Double-receptor-targeting multifunctional iron oxide nanoparticles drug delivery system for the treatment and imaging of prostate cancer

Author

Mohamed O. Abdalla, Clayton Yates, Kyle R. Willian, Shakir Uddin Ahmed, Jesse M. Jaynes, Timothy Turner, and Ahmad Bin Salam

Subjects
0301 basic medicine, Male, Pharmaceutical Science, 02 engineering and technology, Ferric Compounds, targeted drug delivery, chemistry.chemical_compound, Prostate cancer, Drug Delivery Systems, International Journal of Nanomedicine, Drug Discovery, Internalization, Receptor, media_common, Original Research, Cell Death, Chemistry, iron oxide nanoparticles, General Medicine, Hydrogen-Ion Concentration, 021001 nanoscience & nanotechnology, prostate cancer, Magnetic Resonance Imaging, Endocytosis, 3. Good health, Drug delivery, 0210 nano-technology, Iron oxide nanoparticles, hormones, hormone substitutes, and hormone antagonists, endocrine system, Paclitaxel, Cell Survival, Surface Properties, media_common.quotation_subject, Iron, Biophysics, Bioengineering, Biomaterials, 03 medical and health sciences, Cell Line, Tumor, medicine, Animals, Humans, Computer Simulation, Viability assay, Particle Size, LHRH-R, Organic Chemistry, Prostatic Neoplasms, medicine.disease, Urokinase receptor, Drug Liberation, 030104 developmental biology, Targeted drug delivery, Cancer research, Hydrodynamics, Nanoparticles, Peptides, uPAR
Abstract

Md Shakir Uddin Ahmed,1 Ahmad Bin Salam,1 Clayton Yates,1 Kyle Willian,2 Jesse Jaynes,3 Timothy Turner,4 Mohamed O Abdalla5 1Department of Biology, Tuskegee University, Tuskegee, 2Department of Chemistry and Biochemistry, Auburn University, Auburn, 3Department of Environmental Sciences, Tuskegee University, Tuskegee, AL, 4Department of Biology, Jackson State University, Jackson, MS, 5Department of Chemistry, Tuskegee University, Tuskegee, AL, USA Abstract: As an alternative therapeutic treatment to reduce or eliminate the current side effects associated with advanced prostate cancer (PCa) chemotherapy, a multifunctional double-receptor-targeting iron oxide nanoparticles (IONPs) (luteinizing hormone-releasing hormone receptor [LHRH-R] peptide- and urokinase-type plasminogen activator receptor [uPAR] peptide-targeted iron oxide nanoparticles, LHRH-AE105-IONPs) drug delivery system was developed. Two tumor-targeting peptides guided this double-receptor-targeting nanoscale drug delivery system. These peptides targeted the LHRH-R and the uPAR on PCa cells. Dynamic light scattering showed an increase in the hydrodynamic size of the LHRH-AE105-IONPs in comparison to the non-targeted iron oxide nanoparticles (NT-IONPs). Surface analysis showed that there was a decrease in the zeta potential values for drug-loaded LHRH-AE105-IONPs compared to the NT-IONPs. Prussian blue staining demonstrated that the LHRH-AE105-IONPs were internalized efficiently by the human PCa cell line, PC-3. In vitro, magnetic resonance imaging (MRI) results confirmed the preferential binding and accumulation of LHRH-AE105-IONPs in PC-3 cells compared to normal prostate epithelial cells (RC77N/E). The results also showed that LHRH-AE105-IONPs significantly maintained T2 MRI contrast effects and reduced T2 values upon internalization by PC-3 cells. These paclitaxel-loaded double-receptor-targeting IONPs also showed an approximately twofold reduction in PC-3 cell viability compared to NT-IONPs. Keywords: LHRH-R, uPAR, prostate cancer, iron oxide nanoparticles, targeted drug delivery

Published
2017

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