The dynamic interactions of cancer cells with their microenvironment consisting of stromal cells (cellular part) and extracellular matrix (ECM) components (non-cellular) is essential to stimulate the ...heterogeneity of cancer cell, clonal evolution and to increase the multidrug resistance ending in cancer cell progression and metastasis. The reciprocal cell-cell/ECM interaction and tumor cell hijacking of non-malignant cells force stromal cells to lose their function and acquire new phenotypes that promote development and invasion of tumor cells. Understanding the underlying cellular and molecular mechanisms governing these interactions can be used as a novel strategy to indirectly disrupt cancer cell interplay and contribute to the development of efficient and safe therapeutic strategies to fight cancer. Furthermore, the tumor-derived circulating materials can also be used as cancer diagnostic tools to precisely predict and monitor the outcome of therapy. This review evaluates such potentials in various advanced cancer models, with a focus on 3D systems as well as lab-on-chip devices. Video abstract.
Were magnetic materials useful in cancer therapy? Baghban, Roghayyeh; Afarid, Mehrdad; Soleymani, Jafar ...
Biomedicine & pharmacotherapy,
December 2021, 2021-Dec, 2021-12-00, 20211201, 2021-12-01, Letnik:
144
Journal Article
Recenzirano
Odprti dostop
Cancer is one of the major challenges fronting the biomedical basic researches in our time. The study and development of effective therapeutic strategies for cancer therapy are vital. Among the many ...probable core constituents of nanoparticles, magnetite-based nanoparticles have been widely studied for cancer therapy owing to their inherent magnetic features, multifunctional design, biodegradable and biocompatible properties. Magnetic nanoparticles have been also designed for utilizing as contrast enhancer agents for magnetic resonance imaging, drug delivery systems, and most recently as a therapeutic element in inducing cellular death in tumor ablation therapies. This review aimed to provide an overview of the various applications of magnetic nanoparticles and recent achievements in developing these advanced materials for cancer therapy.
Ocular drug delivery is one of the most challenging endeavors among the various available drug delivery systems. Despite having suitable drugs for the treatment of ophthalmic disease, we have not yet ...succeeded in achieving a proper drug delivery approach with the least adverse effects. Nanotechnology offers great opportunities to overwhelm the restrictions of common ocular delivery systems, including low therapeutic effects and adverse effects because of invasive surgery or systemic exposure. The present review is dedicated to highlighting and updating the recent achievements of nano-based technologies for ocular disease diagnosis and treatment. While further effort remains, the progress illustrated here might pave the way to new and very useful ocular nanomedicines.
Despite the existence of numerous eye drops in the market, most of them are not sufficiently effective because of quick clearance and the barriers within the eye. To increase the delivery of the ...drugs to the eye, various new formulations have been explored in recent decades. These formulations aim to enhance drug retention and penetration, while enabling sustained drug release over extended periods. One such innovative approach is the utilization of contact lenses, which were originally designed for cosmetic purposes and vision correction. Contact lenses have appeared as a promising formulation for ocular drug delivery, as they can increase the bioavailability of drugs in the eye and diminish unwanted side effects. They are specifically appropriate for treating chronic eye conditions, making them an area of interest for researchers in the field of ophthalmology. This review outlines the promising potential of nanomaterial-laden contact lenses for diagnosis and treatment of glaucoma. It classifies therapeutic approaches based on nanomaterial type, summarizes diagnostic advances, discusses improvement of contact lenses properties, covers marketing perspectives, and acknowledges the challenges of these innovative contact lenses for glaucoma management.
Although Pichia pastoris is an outstanding host among conventional expression systems for production of recombinant proteins, a new interest has been emerged to this system due to the inherent ...advantages and new developments in this expression host. The potential for secretory and soluble expression of heterologous glycoproteins in P. pastoris proposed this system as a candidate for the production of complex eukaryotic proteins.
Several new developments have occurred in different areas related to P. pastoris expression system including hosts, vectors, glycosylation pattern and fermentation technology. Strain engineering using Crispr/Cas9 technology to produce human-like glycoproteins and protease deficient strains are two new areas of development with high importance.
This review is dedicated to discuss the most important characteristics of P. pastoris with emphasis on new developments, especially in the field of glycoengineering, efficient expression vectors and promoters.
New developments that occurred in the P. pastoris expression system converted this system to a versatile host for the production of complex proteins. This progress paved the way for several proteins to enter the clinical trials or industrial processes with this valuable expression host.
GCK rs780094 polymorphism is a single nucleotide polymorphism that has been associated with obesity, type II diabetes and dyslipidemia in some populations, conditions that highly related to NAFL ...etiology. The present study aimed to evaluate the relationship between NAFLD and rs780094 polymorphism in patients with NAFLD in Tabriz city, northwest of Iran. The rs780094 polymorphism was determined in 74 patients with NAFLD by PCR-RFLP technique. Demographic information was collected using a questionnaire and biochemical analysis was performed using standard laboratory methods.
There was a significant difference between case and control subjects for alanine aminotransferase, aspartate aminotransferase, HDL-C and triglycerides (P < 0.05). Analysis by PCR-RFLP method revealed that there were no significant differences between NAFLD and healthy subjects for rs780094 polymorphism in the study population. The results of this study indicated that rs780094 polymorphism is not associated with NAFLD in subjects from Tabriz city.
The vascular endothelial growth factor (VEGF) signaling pathway has a crucial role in regulating tumor angiogenesis. VEGF-A shows prominent interaction with the VEGF receptor-1 and VEGF receptor-2 on ...the membrane of the endothelial cells. The current study aimed to design and model an anti-VEGF peptide based on VEGFR2 binding regions. The effective amino acid sequences in the interaction of VEGF-A and VEGFR-2 were investigated using Chimera, SPDBV and PyMOL software. The VEGF binding sites on the receptor were determined and used as the basis for peptide design. This sequence was then subjected to random mutagenesis, and the binding affinity of resultant peptides analyzed by Hex 8.0.0 and ClusPro software. Then, GROMACS v5.0.6 has been used for Molecular Dynamics (MD) simulation and assessing the stability of target-ligand complexes. Finally, the chosen peptide with the highest affinity was grafted into two loops of SFTI-1 (sunflower trypsin inhibitor-1) and MCoTI-II (Momordica cochinchinensis trypsin inhibitor-II) frameworks for improving the peptide stability. Among the 18 peptides from the second library, four peptides were opted, of which NGIDFNRDKFLFL showed the highest affinity with a total energy of − 742 kcal/mol. We found that this peptide can bond to the VEGF and block VEGF binding to VEGFR2. The RMSD, RMSF, and H-bonds analysis verified the docking results. The peptide grafted into loop 1 of SFTI-1 increased the peptide-VEGF binding affinity compared to peptide alone. The results showed that in silico design could be used for the identification of efficient anti-angiogenic peptides for potential application in antiangiogenic therapies.
Ocriplasmin (Jetrea) is using for the treatment of symptomatic vitreomacular adhesion. This enzyme undergoes rapid inactivation and limited activity duration as a result of its autolytic nature after ...injection within the eye. Moreover, the proteolytic activity can cause photoreceptor damage, which may result in visual impairment in more serious cases.
The present research aimed to reduce the disadvantages of ocriplasmin using site-directed mutagenesis. To reduce the autolytic activity of ocriplasmin in the first variant, lysine 156 changed to glutamic acid and, in the second variant for the proteolytic activity reduction, alanine 59 mutated to threonine. The third variant contained both mutations. Expression of wild type and three mutant variants of ocriplasmin constructs were done in the Pichia pastoris expression system. The mutant variants were analyzed in silico and in vitro and compared to the wild type. The kinetic parameters of ocriplasmin variants showed both variants with K156E substitution were more resistant to autolytic degradation than wild-type. These variants also exhibited reduced K
and V
values. An increase in their Km values, leading to a decreased catalytic efficiency (the K
/K
ratio) of autolytic and mixed variants. Moreover, in the variant with A59T mutation, K
and V
values have reduced compared to wild type. The mix variants showed the most increase in Km value (almost 2-fold) as well as reduced enzymatic affinity to the substrate. Thus, the results indicated that combined mutations at the ocriplasmin sequence were more effective compared with single mutations.
The results indicated such variants represent valuable tools for the investigation of therapeutic strategies aiming at the non-surgical resolution of vitreomacular adhesion.
Ocriplasmin has been developed for the induction of posterior vitreous detachment in patients with vitreomacular adhesion. At physiological pH, ocriplasmin is susceptible to autolytic and proteolytic ...degradation, limiting its activity duration. These undesirable properties of ocriplasmin can be reduced by site-directed mutagenesis, so that its enzymatic activities can be augmented. This study aimed to design ocriplasmin variants with improved biological/physicochemical characteristics via bioinformatics tools.
This study was performed in Tabriz University of Medical Sciences, Tabriz, Iran, 2019. Through site-directed mutagenesis, three ocriplasmin variants were designed. Structural analysis was performed on the wild-type variant and the mutant variants using the Protein Interactions Calculator (PIC) server. The interactions between the S-2403 substrate and the ocriplasmin variants were studied by molecular docking simulations, and binding capability was evaluated by the calculation of free binding energy. The conformational features of protein-substrate complex systems for all the variants were evaluated using molecular dynamic simulations at 100 nanoseconds.
The structural analysis of ocriplasmin revealed that the substitution of threonine for alanine 59 significantly reduced proteolytic activity, while the substitution of glutamic acid for lysine 156 influenced autolytic function. The molecular docking simulation results indicated the appropriate binding of the substrate to the ocriplasmin variants with high-to-low affinities. The binding affinity of the wild-type variant for the substrate was higher than that between the mutant variants and the substrate. Simulation analyses, consisting of the root-mean-square deviation, the root-mean-square fluctuation, and the center-of-mass average distance showed a higher affinity of the substrate for the wild type than for the mutant variants.
The mutational analysis of ocriplasmin revealed that A59T and K156E mutagenesis could be used for the development of a new variant with higher therapeutic efficacy.
Purpose: Ocriplasmin (Jetrea TM) is a FDA approved recombinant enzyme utilized in the treatment of vitreomacular adhesion (VMA). This is a recombinant C-terminal fragment of human plasmin produced ...using yeast Pichia pastoris. Since ocriplasmin does not contain any O-or N-glycosylation or some other post-translational modifications, bacterial expression systems such as Escherichia coli could be considered as an economical host for recombinant expression. In the present study, we aimed to evaluate the efficiency of E. coli expression system for high-level expression of recombinant ocriplasmin. Methods: The gene coding for ocriplasmin was cloned and expressed in E. coli BL21. The bacterial cells were cultured on large scale and the expressed recombinant protein was purified using Ni-NTA chromatography. Refolding of denatured ocriplasmin to active enzyme was carried out by the stepwise removal of denaturant. The identity of recombinant ocriplasmin was confirmed using western blotting and ELISA assays. The presence of the active ocriplasmin was monitored by the hydrolytic activity assay against the chromogenic substrate S-2403. Results: The final yield of E. coli BL21-produced ocriplasmin was approximately 1 mg/mL which was greater than that of P. pastoris. Using western blotting and ELISA assay, the identity of recombinant ocriplasmin was confirmed. The hydrolysis of chromogenic substrate S-2403 verified the functional activity of E. coli produced ocriplasmin. Conclusion: The results of this study indicated that E. coli could be used for high level expression of ocriplasmin. Although the recombinant protein was expressed as inclusion body, the stepwise refolding leads to the biologically active proteins.