Vol 25, No 1 (2024)
- Year: 2024
- Articles: 10
- URL: https://ter-arkhiv.ru/1389-2037/issue/view/10129
Life Sciences
Tribute to Prof. Ben M. Dunn: A Remarkable Biochemist and Editor-in-Chief of Current Protein & Peptide Science and Protein & Peptide Letters
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Preface
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Enzymatic Targets in the Anticancer Drug Discovery
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Mechanism-based Suppression of Cancer by Targeting DNA-Replicating Enzymes
Abstract
The human genetic structure undergoes continuous wear and tear process due to the mere presence of extrinsic as well as intrinsic factors. In normal physiological cells, DNA damage initiates various checkpoints that may activate the repair system or induce apoptosis that helps maintain cellular integrity. While in cancerous cells, due to alterations in signaling pathways and defective checkpoints, there exists a marked deviation of error-free DNA repairing/synthesis. Currently, cancer therapy targeting the DNA damage response shows significant therapeutic potential by tailoring the therapy from non-specific to tumor-specific activity. Recently, numerous drugs that target the DNA replicating enzymes have been approved or some are under clinical trial. Drugs like PARP and PARG inhibitors showed sweeping effects against cancer cells. This review highlights the mechanistic study of different drug categories that target DNA replication and thus depicts the futuristic approach of targeted therapy.
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PI3K Signaling Pathways as a Molecular Target for Glioblastoma Multiforme
Abstract
Glioblastoma multiforme (GBM) is the most common type of cancer that affects the central nervous system (CNS). It currently accounts for about 2% of diagnosed malignant tumors worldwide, with 296,000 new cases reported per year. The first-choice treatment consists of surgical resection, radiotherapy, and adjuvant chemotherapy, which increases patients' survival by 15 months. New clinical and pre-clinical research aims to improve this prognosis by proposing the search for new drugs that effectively eliminate cancer cells, circumventing problems such as resistance to treatment. One of the promising therapeutic strategies in the treatment of GBM is the inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway, which is closely related to the process of tumor carcinogenesis. This review sought to address the main scientific studies of synthetic or natural drug prototypes that target specific therapy co-directed via the PI3K pathway, against human glioblastoma.
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Mechanisms Involved in the Therapeutic Effect of Cannabinoid Compounds on Gliomas: A Review with Experimental Approach
Abstract
Introduction:Brain tumors have high morbidity and mortality rates, accounting for 1.4% of all cancers. Gliomas are the most common primary brain tumors in adults. Currently, several therapeutic approaches are used; however, they are associated with side effects that affect patientsquality of life. Therefore, further studies are needed to develop novel therapeutic protocols with a more favorable side effect profile. In this context, cannabinoid compounds may serve as potential alternatives.
Objective:This study aimed to review the key enzymatic targets involved in glioma pathophysiology and evaluate the potential interaction of these targets with four cannabinoid derivatives through molecular docking simulations.
Methods:Molecular docking simulations were performed using four cannabinoid compounds and six molecular targets associated with glioma pathophysiology.
Results:Encouraging interactions between the selected enzymes and glioma-related targets were observed, suggesting their potential activity through these pathways. In particular, cannabigerol showed promising interactions with epidermal growth factor receptors and phosphatidylinositol 3- kinase, while Δ-9-tetrahydrocannabinol showed remarkable interactions with telomerase reverse transcriptase.
Conclusion:The evaluated compounds exhibited favorable interactions with the analyzed enzymatic targets, thus representing potential candidates for further in vitro and in vivo studies.
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In Silico and In vitro Analysis of Phenolic Acids for Identification of Potential DHFR Inhibitors as Antimicrobial and Anticancer Agents
Abstract
Background:DHFR is an indispensable enzyme required for the survival of almost all prokaryotic and eukaryotic cells, making it an attractive molecular target for drug design.
Objective:In this study, a combined in silico and in vitro approach was utilized to screen out potential anticancer and antimicrobial agents by using DHFR PDB ID 2W9S (for antimicrobial) and 1U72 (for anticancer).
Methods:Computational work was performed using Maestro Schrodinger Glide software. The DHFR inhibitory activity of the selected compounds was assessed using the DHFR test kit (CS0340-Sigma- Aldrich).
Results:Exhaustive analysis of in-silico results revealed that some natural phenolic acids have a good docking score when compared to standards, i.e., trimethoprim and methotrexate, and have astonishing interactions with crucial amino acid residues available in the binding pocket of DHFR, such as Phe 92, Asp 27, Ser 49, Asn 18, and Tyr 98. In particular, digallic acid and chlorogenic acid have amazing interactions with docking scores of -9.9 kcal/mol and -9.6 kcal/mol, respectively, for the targeted protein 2W9S. Docking scores of -10.3 kcal/mol and -10.2 kcal/mol, respectively, for targeted protein 1U72. The best hits were then tested in vitro to evaluate the DHFR inhibitory activity of the compounds. DHFR inhibition activity results are in correlation with molecular docking results.
Conclusion:In silico and in vitro results confirmed the good binding and inhibitory activity of some phenolic acids to the modeled target proteins. Among all the studied natural phenolic acids, chlorogenic acid, digallic acid, and rosmarinic acid appeared to be the most potential leads for future chemical alteration. This study can provide significant speculative guidance for the design and development of potent DHFR inhibitors in the future by using these compounds as leads.
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Unfolded Protein Response Signaling in Hepatic Stem Cell Activation in Liver Fibrosis
Abstract
Frequent exposure to various external and internal adverse forces (stresses) disrupts cell protein homeostasis through endoplasmic reticulum (ER) capacity saturation. This process leads to the unfolded protein response (UPR), which aims to re-establish/maintain optimal cellular equilibrium. This complex mechanism is involved in the pathogenesis of various disorders, such as metabolic syndrome, fibrotic diseases, neurodegeneration, and cancer, by altering cellular metabolic changes integral to activating the hepatic stellate cells (HSCs). The development of hepatic fibrosis is one of the consequences of UPR activation. Therefore, novel therapies that target the UPR pathway effectively and specifically are being studied. This article covers the involvement of the UPR signaling pathway in cellular damage in liver fibrosis. Investigating the pathogenic pathways related to the ER/UPR stress axis that contribute to liver fibrosis can help to guide future drug therapy approaches.
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Intercellular Interactions Mediated by HGF And TGF-Β Promote the 3D Spherical and Xenograft Growth of Liver Cancer Cells
Abstract
Background:Recently, the importance of the interactions between liver cancer cells and fibroblasts has been increasingly recognized; however, many details remain to be explored
Methods:In this work, we first studied their intercellular interactions using conditioned medium from mouse embryonic fibroblasts (MEFs), then through a previously established coculture model.
Results:Culturing in a conditioned medium from MEFs could significantly increase the growth, migration, and invasion of liver cancer cells. The coculture model further demonstrated that a positive feedback loop was formed between transforming growth factor-β (TGF-β) from HepG2 cells and mHGF (mouse hepatocyte growth factor) from MEFs during coculture. In this feedback loop, c-Met expression in HepG2 cells was significantly increased, and its downstream signaling pathways, such as Src/FAK, PI3K/AKT, and RAF/MEK/ERK, were activated. Moreover, the proportion of activated MEFs was also increased. More importantly, the growth-promoting effects caused by the interaction of these two cell types were validated in vitro by a 3D spheroid growth assay and in vivo by a xenograft mouse model.
Conclusion:Collectively, these findings provide valuable insights into the interactions between fibroblasts and liver cancer cells, which may have therapeutic implications for the treatment of liver cancer
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In Vitro Antibacterial Activity of a Novel Acid-Activated Antimicrobial Peptide against Streptococcus mutans
Abstract
Background:Dental caries is an oral disease associated with infection by microbial biofilm. The metabolic activity of cariogenic bacteria results in a pH decrease in the plaque biofilm, causing tooth demineralization. This acidic environment favors the growth of cariogenic bacteria that are highly resistant to strong acids, which, in turn, produce more acid resulting in a further decrease in the pH of the plaque biofilm. Therefore, the strategy of utilizing the acidic dental plaque microenvironment to prevent and treat dental caries has become a hot research topic in recent years, such as the development of pH-sensitive drug delivery systems.
Aims:Design of a new acid-activated antibacterial peptide.
Objective:To design and synthesis an acid targeted antimicrobial peptide with the GWHHFFHFFHFF sequence.
Methods:Minimum inhibitory concentration (MIC) and minimum bacterial concentration (MBC) testing confirmed its antibacterial activity. Propidium iodide (PI) staining was used to detect nucleic acid leakage. Determination of anti-biofilm activity by biofilm inhibition assay. A phototoxicity study confirmed the phototoxicity of PPIX-P12.
Results:MIC and MBC testing confirmed that P12 possessed acid-activated anti-Streptococcus mutans activity. Bactericidal kinetic experiments and propidium iodide (PI) staining experiments showed that P12 killed planktonic S. mutans UA159 cells leading to the leakage of nucleic acids in the acidic medium. Moreover, P12 showed acid-activated anti-biofilms at the early and mature biofilm stages. P12 was conjugated with the phototherapeutic agent protoporphyrin IX (PpIX) to construct the protoporphyrin derivative PpIX-P12. In vitro experiments revealed that PpIX-P12 displayed better antibacterial activity in pH 5.5 medium than in pH 7.2 medium.
Conclusion:In conclusion, we designed an acid-activated AMP, which had no antimicrobial activity at neutral pH, but had antimicrobial activity at an acidic pH.
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