Evaluation of suppressor behavior of guanidine-derived metformin and galegine as novel potential drugs for cancer treatment: an in silico study.

There are some natural products from plants that can prevent and treat disease. Metformin, a derivative of galegine, is the basic drug to treat diabetes. Moreover, this molecule has anticancer properties that inhibit cancer cell growth and proliferation. In this study, the main interactions of galegine and metformin with various cancer-involved proteins, including mitochondrial alpha-glycerophosphate dehydrogenase, yeast NADH dehydrogenase, and transforming growth factor-ß1, were surveyed by molecular docking and molecular dynamics simulations. The results showed that each of the proteins makes complexes with the ligands via favorable non-bonded interactions, especially hydrogen bond interactions. There is greater stability for complexes containing galegine based on the root mean square deviation results. The higher structure compactness is also found in galegine receptors than in metformin receptors. Calculation of ΔGbinding, using the MM/PBSA methodology, shows that the binding energy values for metformin and galegine in interaction with each of the receptors are almost the same, and galegine has similar binding properties with metformin in interaction with the studied protein receptors. Therefore, galegine, a natural ingredient with better binding properties to cancer-involved proteins than metformin (with various side effects), can be applied as a new drug for cancer treatment.

Development of carboxymethyl cellulose-based nanocomposite incorporated with ZnO nanoparticles synthesized by cress seed mucilage as green surfactant.

This study aimed to enhance carboxymethyl cellulose (CMC)-based films by incorporating zinc oxide nanoparticles (ZnO NPs) and cress seed mucilage (CSM), with a view to augmenting the physical, mechanical, and permeability properties of the resulting nanocomposite films. For the first time, CSM was exploited as a green surfactant to synthetize ZnO NPs using hydrothermal method. Seven distinct film samples were meticulously produced and subjected to a comprehensive array of analyses. The findings revealed that the incorporation of CSM/ZnO-5 % improved the physical properties of the films, demonstrating a significant reduction in moisture content and water vapor permeability (WVP). Increasing the concentration of NPs in conjunction with CSM markedly decreased the solubility of the nanocomposites by up to 56 %. The films containing CSM/ZnO showed higher tensile strength and elongation at the break values. The UV absorption of the films exhibited a substantial rise with the addition of ZnO NPs, particularly with an increased content in the presence of CSM. The thermal stability of nanocomposites containing a high concentration of CSM/ZnO exhibited an improvement compared to the control sample. In light of these results, the CMC/CSM/ZnO-5 % film emerges as a promising candidate for a biocompatible packaging material, exhibiting favorable physical characteristics.

Study on the impact of temperature, salts, sugars and pH on dilute solution properties of Lepidium perfoliatum seed gum.

The functional properties of food gums are remarkably affected by the quality of solvent/cosolutes and temperature in a food system. In this work, for the first time, the chemical characterizations and dilute solution properties of Lepidium perfoliatum seed gum (LPSG), as an emerging carbohydrate polymer, were investigated. It was found that xylose (14.27%), galacturonic acid (10.70%), arabinose (9.07%) and galactose (8.80%) were the main monosaccharaide components in the LPSG samples. The uronic acid content of LPSG samples was obtained to be 14.83%. The average molecular weight and polydispersity index of LPSG were to be 2.34 × 105 g/mol and 3.3, respectively. As the temperature was increased and the pH was decreased and the concentration of cosolutes (Na+, Ca2+, sucrose and lactose) presented in the LPSG solutions was enhanced, the intrinsic viscosity [η] and coil dimension (R coil , V coil , υ s ) of LPSG molecular chains decreased. Activation energy and chain flexibility of LPSG were estimated to be 0.46 × 107 J/kg.mol and 553.08 K, respectively. The relative stiffness parameter (B) of LPSG in the presence of Ca2+ (0.079) was more than that of Na+ (0.032). Incorporation of LPSG into deionized water (0.2%, w/v) diminished the surface activity from 76.75 mN/m to 75.70 mN/m. Zeta potential (ζ) values (-46.85 mV--19.63 mV) demonstrated that dilute solutions of LPSG had strong anionic nature in the pH range of 3-11. The molecular conformation of LPSG was random coil in all the selected solution conditions. It can be concluded that temperature and presence of cosolutes can significantly influence on the LPSG properties in the dilute systems.

Innovative construction of a novel lanthanide cerate nanostructured photocatalyst for efficient treatment of contaminated water under sunlight.

Herein, we have developed Ln2Ce2O7 (Ln = Er, Ho) ceramic nanostructures through a rapid and green sonochemical approach and scrutinized their photocatalytic efficiency toward degradation of toxic pollutants under sunlight. Salvia rosmarinus extract is utilized as a morphology-directing agent in the sono-synthesis of the nanostructured Ln2Ce2O7 (Ln = Er, Ho), for the first time. Comprehensive characterization utilizing different techniques demonstrated that introducing of rare-earth metals, erbium and holmium, affected the textural, morphological, and optical features of the nanostructured ceria. The energy gap for pure cerium dioxide nanostructure was estimated to be 3.09 eV, while the energy gap for Ho2Ce2O7 and Er2Ce2O7 nanostructure was estimated at 2.9 and 2.66 eV, respectively. The narrowing of the energy gap was observed as a result of the introduction of rare-earth metals, erbium and holmium, especially erbium, into the nanostructured ceria. Investigation of the photocatalytic decomposition of various contaminants revealed that the introduction of erbium has remarkably enhanced the photocatalytic activity of nanostructured ceria. High photocatalytic performance (98.9%) and rate constant (0.0727 min-1) was observed for the Er2Ce2O7 nanostructure in the removal of eriochrome Black T. Improving the optical features of ceria nanostructure as well as enhancing its specific area were reasons that could increase the photocatalytic efficiency. The photocatalytic decomposition reactions in the removal of toxic contaminants were well accorded with the Pseudo-first order reaction kinetics. Besides, the nanostructured Er2Ce2O7 maintained its efficiency after ten reaction cycles and did not denote any notable decline in efficiency. The use of this novel porous nanostructure can be a potentially efficient solution for water treatment.

Preparation of cerium-curcumin and cerium-quercetin complexes and their LEDs irradiation assisted anticancer effects on MDA-MB-231 and A375 cancer cell lines.

Cancer remains common and often is difficult to eradicate. In particular resistant forms like triple negative breast cancer and melanoma generally allow for very short survival. Curcumin and quercetin as two important polyphenols from plants which have different biological roles, potentially including anti-cancer effect. But their clinical application is limited due to poor solubility in aqueous medium. Photodynamic therapy (PDT) is a cancer treatment using select chemical compounds as photosensitizers, which when activated by light create toxic singlet oxygen. Studies done on plant based photosensitizers such as curcumin and quercetin have shown the ability to ablate tumors. Here we discuss using them as improved PS by making their complex with cerium ions as a delivery system for MDA-MB-231 and A375 cancer cell lines treatment. For this purpose, the MDA-MB-231 human breast cancer cell line exposed to red light irradiation (as pretreatment) then treated with curcumin and quercetin alone and also their complex with cerium. In another study the cells treated with curcumin-cerium and quercetin-cerium complex and then irradiated with blue light (photodynamic treatment). Cell survival and apoptosis were determined using MTT and fluorescence microscopy. The result showed that curcumin and quercetin in complex with cerium ions have better toxic effect against both breast and melanoma cancer cells as compared to each compound alone. The finding revealed that curcumin and quercetin in cerium complex could be considered as a new approach in the photodynamic treatment of breast and melanoma cancer cells.

Biological properties the novel application of N-trimethyl chitosan nanospheres as a stabilizer and preservative in tetanus vaccine.

PURPOSE: Chitosan is a natural polymer that has excellent properties include biocompatibility, biodegradability, no cytotoxicity, high charge density, low cost, mucoadhesive, permeation enhancing (ability to cross tight junction), and immunomodulating ability that makes the spectrum of its applicability much broader. This study was conducted to investigate the stabilizing, preservative and immunogenicity properties of N-trimethyl chitosan nanospheres (N-TMCNS). MATERIALS AND METHODS: The tetanus toxoid (TT) was encapsulated into N-TMCNS and then characterized by scanning electron microscope, atomic force microscope, and dynamic light scattering. For stabilizer assay of N-TMCNS after storage of TT-N-TMCNS at different temperatures for 3 weeks, they were used for immunization of mice and different temperatures groups' anti-TT-N-TMCNS production compared with other groups. Finally, the immunized mice were challenged with tetanus toxin. The preservation activity of TT-N-TMCNS against Escherichia coli was compared with thimerosal formulated TT. RESULTS: Our results revealed that heat-treated TT-N-TMCNS could induce higher titer of neutralizing immunoglobulin G in compared to TT vaccine and was able to protect the mice better than TT vaccine in challenge test. Furthermore, N-TMCNS as a preservative inhibited the growth of E. coli more effective than thimerosal. CONCLUSION: Overall, the obtained results indicated that the N-TMCNS is one of the best stabilizer and preservative agent that can be used in the formulation of TT vaccine.

Rational MD simulations for improvement the affinity of nanobody against PlGF (placenta growth factor): mutagenesis based on electrostatic interactions.

AbbreviationsCOMcenter of mass distanceMDmolecular dynamicsMM-PBSAMolecular Mechanics Poisson-Boltzmann Surface AreaNbnanobodyPlGFplacenta growth factorRgradius of gyrationRMSDroot mean-square deviationSASAsolvent-accessible surface areaVEGFvascular endothelial growth factor.

Experimental investigation and molecular dynamics simulation of the binding of ellagic acid to bovine liver catalase: Activation study and interaction mechanism.

Ellagic acid (ELA), as a polyphenolic natural compound and food additive, which has reported to possess anti-carcinogenic, antioxidant, antidepressant, ameliorative and anti-mutagenic effects. In the current work, the effects of ELA on the conformation and catalytic activity of catalase were investigated by using spectroscopic techniques including ultraviolet visible (UV-vis), fluorescence, synchronous fluorescence and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy as well as molecular dynamics (MD) simulation. Kinetic studies showed that the enzymatic activity of catalase increases in the presence of ELA (almost 2-fold higher than free enzyme activity). Moreover, analysis of fluorescence data revealed two binding sites for ELA on the catalase and static type of quenching mechanism. The binding constants between ELA and catalase were obtained to be 47.35 × 107 M-1 (at 298 K) and 17.60 × 107 M-1 (at 310 K) and the binding distance was calculated to be 2.83 nm. Thermodynamic data showed that hydrogen bonds have a main role in the ELA-catalase complex formation. The best binding sites for ELA were, in the middle of ß-barrel and wrapping domain and in the middle of ß-barrel and helical domain, according to molecular docking data. MD simulation results were confirmed that ELA can increase catalase activity through increasing the distance between an upper side α-helix structure and a down side random coil structure.

Comparative study of photodynamic activity of methylene blue in the presence of salicylic acid and curcumin phenolic compounds on human breast cancer.

Curcumin and salicylic acid are both phenolic compounds and they can both affect cancer treatment efficacy. In this study, the effects of methylene blue-curcumin (CU-MB) and methylene blue-salicylic acid (SA-MB) ion pair complexes on MDA-MB-231 human breast cancer cells are studied. According to the thermodynamic parameters, the stability of curcumin and salicylic acid complexes ion pair complexes was compared. The free energy of ion pair interactions was calculated based on binding constants. A comparison of the free energies of the complexes (CU-MB: ∆G°b1 = - 21.11 kJ/mol and ∆G°b2 = - 8.37 kJ/mol, SA-MB: ∆G°b1 = - 12.92 kJ/mol and ∆G°b2 = - 9.02 kJ/mol) indicates that the interaction of methylene blue in first binding interaction with curcumin is greater than that of methylene blue with salicylic acid. Electrostatic interactions are the main forces in the binding of both compounds to methylene blue. All forces are inter-molecular physical interactions. The results of cellular experiments show that ion pairing has enhanced the reduction of cell viability. By increasing molecular stability and prevention of dimerization of methylene blue, the cell killing potential of methylene blue increases and it subsequently causes enhancement of photodynamic efficacy.

Rational affinity enhancement of fragmented antibody by ligand-based affinity improvement approach.

Antibody engineering is now a noteworthy area in biopharmaceuticals as the next generation of marketed antibodies is engineered antibodies such as affinity- or stability-improved antibodies, fragmented or fused antibodies, antibody drug conjugates (ADCs), and PEGylated antibody fragments. In the current study, affinity enhancement of Nb against PlGF was performed by an in silico affinity maturation and molecular dynamics (MD) simulation. First, 300 single-point mutants were designed by identifying the residues involved in interaction with PlGF and different energy distributions. An energy based screening was performed to select best single-point mutants. Additionally, one variant containing two mutations was designed based on the selected single-point mutants. Finally, mutants-PlGF complexes were analyzed in details by all atom MD simulation. Trajectory analysis revealed that in both single (L112H, S31D, A97K, and R45E) and double (S31D & R45E) mutants, the free binding energies and the stability of complexes were significantly improved. The highest increment in affinity was observed for S31D mutant due to substantial increase in polar and electrostatic interactions. The secondary structure of Nb was intact in all variants and a shrinkage of PlGF over Nb was observed in all mutant-PlGF complexes during simulation. In addition, contact area and hydrogen-bond analysis as well as distance measurement in mutants-PlGF complexes also confirmed the affinity enhancement of variants relative to the native form. Our study showed that ligand-based affinity improvement could be considered as a promising approach for designing high affinity fragmented antibodies.

Interaction mechanism of insulin with ZnO nanoparticles by replica exchange molecular dynamics simulation.

The interaction of ZnO nanoparticles with biological molecules such as proteins is one of the most important and challenging problems in molecular biology. Molecular dynamics (MD) simulations are useful technique for understating the mechanism of various interactions of proteins and nanoparticles. In the present work, the interaction mechanism of insulin with ZnO nanoparticles was studied. Simulation methods including MD and replica exchange molecular dynamics (REMD) and their conditions were surveyed. According to the results obtained by REMD simulation, it was found that insulin interacts with ZnO nanoparticle surface via its polar and charged amino acids. Unfolding insulin at ZnO nanoparticle surface, the terminal parts of its chains play the main role. Due to the linkage between chain of insulin and chain of disulfide bonds, opposite directional movements of N terminal part of chain A (toward nanoparticle surface) and N termini of chain B (toward solution) make insulin unfolding. In unfolding of insulin at this condition, its helix structures convert to random coils at terminal parts chains.

Graphene oxide-methylene blue nanocomposite in photodynamic therapy of human breast cancer.

The interaction of methylene blue (MB) as a photosensitizer with graphene oxide nano-sheets (GO) was examined in aqueous solution using UV-vis spectrophotometric techniques. MB-GO composites were prepared by mixing the solutions of GO nano-sheets and methylene blue due to interacting of the cationic methylene blue photosensitizer via electrostatic and π-π stacking or hydrophobic cooperative interactions. The cell killing potential of nanocomposite was examined on the MDA-MB-231 breast cancer cells in the absence and presence of red LED irradiation. The results demonstrated that the MB-GO nanocomposite has good performance in photodynamic therapy (PDT) during red LED irradiation. The cytotoxicity of nanocomposite caused reducing cell viability up to 20%. These effects would be due to the nano size structure of composite that could lead to effective cellular penetration. Also the significant difference has seen in lower concentrations of MB and MB-GO nanocomposite. The results show more than 40% increases in cell killing potential in lower concentrations of nanocomposite by using 2.5 µg/mL of each compound. The ratio of GO/MB can affect the interaction and higher ratios of graphene oxide (GO/MB > 1) can induce dimerization of MB. In lower concentrations and ratios of (GO/MB < 1) the free MB concentration increases and the electron shuttling effect of GO in photo activity decreases - which could affect the photocatalytic yield in PDT. The cell viability measurements confirm these effects on cancer cell killing potential of nanocomposite. According to microscopic and PDT assay results, the nanocomposite distribution and diffusion in cells enhanced the photochemical reaction yield in photodynamic therapy of MDA-MB-231 breast cancer cell line.

Interaction of insulin with colloidal ZnS quantum dots functionalized by various surface capping agents.

Interaction of quantum dots (QDs) and proteins strongly influenced by the surface characteristics of the QDs at the protein-QD interface. For a precise control of these surface-related interactions, it is necessary to improve our understanding in this field. In this regard, in the present work, the interaction between the insulin and differently functionalized ZnS quantum dots (QDs) were studied. The ZnS QDs were functionalized with various functional groups of hydroxyl (OH), carboxyl (COOH), amine (NH2), and amino acid (COOH and NH2). The effect of surface hydrophobicity was also studied by changing the alkyl-chain lengths of mercaptocarboxylic acid capping agents. The interaction between insulin and the ZnS QDs were investigated by fluorescence quenching, synchronous fluorescence, circular dichroism (CD), and thermal aggregation techniques. The results reveal that among the studied QDs, mercaptosuccinic acid functionalized QDs has the strongest interaction (∆G°=-51.50kJ/mol at 310K) with insulin, mercaptoethanol functionalized QDs destabilize insulin by increasing the beta-sheet contents, and only cysteine functionalized QDs improves the insulin stability by increasing the alpha-helix contents of the protein, and. Our results also indicate that by increasing the alkyl-chain length of capping agents, due to an increase in hydrophobicity of the QDs surface, the beta-sheet contents of insulin increase which results in the enhancement of insulin instability.

Antichaperone activity and heme degradation effect of methyl tert-butyl ether (MTBE) on normal and diabetic hemoglobins.

Because of the extensive use of methyl tert-butyl ether (MTBE) as an additive to increase the octane quality of gasoline, the environmental pollution by this compound has increased in recent decades. Environmental release of MTBE may lead to its entry to the blood stream through inhalation or drinking of contaminated water, and its interactions with biological molecules such as proteins. The present study was proposed to comparatively investigate the interactions of MTBE with hemoglobin (Hb) from diabetic and nondiabetic individuals using various spectroscopic methods including UV-visible, fluorescence, chemiluminescence, and circular dichroism. These results demonstrated the effects of MTBE on heme degradation of Hb and the reaction of these degradation products with water generating reactive oxygen species. Interaction of Hb with MTBE enhanced its aggregation rate and decreased lag time, indicating the antichaperone activity of MTBE upon interaction with Hb. Furthermore, the diabetic Hb showed more severe effects of MTBE, including heme degradation, reactive oxygen species production, unfolding, and antichaperone behavior than the nondiabetic Hb. The results from molecular docking suggested that the special interaction site of MTBE in the vicinity of Hb heme group is responsible for heme degradation.

Affinity enhancement of nanobody binding to EGFR: in silico site-directed mutagenesis and molecular dynamics simulation approaches.

Epidermal growth factor receptor (EGFR), a transmembrane glycoprotein, is overexpressed in many cancers such as head-neck, breast, prostate, and skin cancers for this reason it is a good target in cancer therapy and diagnosis. In nanobody-based cancer diagnosis and treatment, nanobodies with high affinity toward receptor (e.g. EGFR) results in effective treatment or diagnosis of cancer. In this regard, the main aim of this study is to develop a method based on molecular dynamic (MD) simulations for designing of 7D12 based nanobody with high affinity compared with wild-type nanobody. By surveying electrostatic and desolvation interactions between different residues of 7D12 and EGFR, the critical residues of 7D12 that play the main role in the binding of 7D12 to EGFR were elucidated and based on these residues, five logical variants were designed. Following the 50 ns MD simulations, pull and umbrella sampling simulation were performed for 7D12 and all its variants in complex with EGFR. Binding free energy of 7D12 (and all its variants) with EGFR was obtained by weighted histogram analysis method. According to binding free energy results, GLY101 to GLU mutation showed the highest binding affinity but this variant is unstable after 50 ns MD simulations. ALA100 to GLU mutation shows suitable binding enhancement with acceptable structural stability. Suitable position and orientation of GLU in residue 100 of 7D12 against related amino acids of EGFR formed some extra hydrogen and electrostatic interactions which resulted in binding enhancement.

Unfolding of insulin at the surface of ZnO quantum dots.

ZnO quantum dots (QDs) have been used in many biomedical applications such as bioimaging, cancer treatments and etc. Crystallinity, particle size, optical absorption and photoluminescence spectra of ZnO QDs were analyzed by X-ray diffraction (XRD), transmission electron microscopy (TEM), UV-vis absorption spectroscopy and fluorescence spectroscopy respectively. Interaction of ZnO QDs with insulin was investigated by fluorescence quenching, circular dichroism (CD), isothermal titration calorimetry (ITC) and thermal aggregation tests. The fluorescence quenching results showed a static type quenching along with red shift in synchronize fluorescence (a sign of protein unfolding). CD spectroscopy results also confirmed this unfolding and show a reduction in alpha helices content of insulin in contact with ZnO QDs and their conversion to random coils. According to ITC results, the ΔG, ΔH and binding constant of this interaction are -32.35 kJ/mol, -43.21 kJ/mol and 4.69 × 10(5) M(-1), respectively. Thermal aggregation test showed fast aggregation of insulin in the presence of ZnO QDs. Therefore in biological application of ZnO QDs such as bioimaging, presence of such QDs in vicinity of insulin could unfold this protein.