Enzyme-responsive mannose-grafted magnetic nanoparticles for breast and liver cancer therapy and tumor-associated macrophage immunomodulation.

BACKGROUND: Chemo-immunotherapy modifies the tumor microenvironment to enhance the immune response and improve chemotherapy. This study introduces a dual-armed chemo-immunotherapy strategy combating breast tumor progression while re-polarizing Tumor-Associated Macrophage (TAM) using prodigiosin-loaded mannan-coated magnetic nanoparticles (PG@M-MNPs). METHODS: The physicochemical properties of one-step synthetized M-MNPs were analyzed, including X-ray diffraction, FTIR, DLS, VSM, TEM, zeta potential analysis, and drug loading content were carried out. Biocompatibility, cancer specificity, cellular uptake, and distribution of PG@M-MNPs were investigated using fluorescence and confocal laser scanning microscopy, and flow cytometry. Furthermore, the expression levels of IL-6 and ARG-1 after treatment with PG and PG@M-MNPs on M1 and M2 macrophage subsets were studied. RESULTS: The M-MNPs were successfully synthesized and characterized, demonstrating a size below 100 nm. The release kinetics of PG from M-MNPs showed sustained and controlled patterns, with enzyme-triggered release. Cytotoxicity assessments revealed an enhanced selectivity of PG@M-MNPs against cancer cells and minimal effects on normal cells. Additionally, immuno-modulatory activity demonstrates the potential of PG@M-MNPs to change the polarization dynamics of macrophages. CONCLUSION: These findings highlight the potential of a targeted approach to breast cancer treatment, offering new avenues for improved therapeutic outcomes and patient survival.

Novel Benzotriazole-ß-lactam Derivatives as Antimalarial Agents: Design, Synthesis, Biological Evaluation and Molecular Docking Studies.

Many people around the world suffer from malaria, especially in tropical or subtropical regions. While malaria medications have shown success in treating malaria, there is still a problem with resistance to these drugs. Herein, we designed and synthesized some structurally novel benzotriazole-ß-lactams using 2-(1H-benzo[d][1,2,3]triazol-1-yl)acetic acid as a key intermediate. To synthesize the target molecules, the ketene-imine cycloaddition reaction was employed. First, The reaction of 1H-benzo[d][1,2,3]triazole with 2-bromoacetic acid in aqueous sodium hydroxide yielded 2-(1H-benzo[d][1,2,3]triazol-1-yl)acetic acid. Then, the treatment of 2-(1H-benzo[d][1,2,3]triazol-1-yl)acetic acid with tosyl chloride, triethyl amine, and Schiff base provided new ß-lactams in good to moderate yields.The formation of all cycloadducts was confirmed by elemental analysis, FT-IR, NMR and mass spectral data. Moreover, X-ray crystallography was used to determine the relative stereochemistry of 4a compound. The in vitro antimalarial activity test was conducted for each compound against P. falciparum K1. The IC50 values ranged from 5.56 to 25.65 µM. A cytotoxicity profile of the compounds at 200 µM final concentration revealed suitable selectivity of the compounds for malaria treatment. Furthermore, the docking study was carried out for each compound into the P. falciparum dihydrofolate reductase enzyme (PfDHFR) binding site to analyze their possible binding orientation in the active site.

Peripapillary vessel density in healthy people, primary open-angle glaucoma, and normal-tension glaucoma.

OBJECTIVE: To compare peripapillary vessel density using optical coherence tomography angiography (OCT-A) in eyes of healthy people, primary open-angle glaucoma (POAG), and normal-tension glaucoma (NTG). METHODS: Thirty patients with POAG, 27 patients with NTG, and 29 healthy individuals in the control group were assessed. Capillary vessels in peripapillary retinal nerve fiber layer (RNFL) represented by whole image RPC (radial peripapillary capillary) density in an AngioDisc scan 4.5 × 4.5 mm centered on the optic disc, and ONH morphological variables (disc area, rim area, cup to disc area ratio (CDR)), and average peripapillary RNFL thickness were measured. RESULTS: Differences in mean RPC, RNFL, disc area, rim area, and CDR between the groups were statistically significant (P < 0.05). The difference in RNFL thickness and rim area was not significant between NTG and healthy groups, while RPC and CDR showed a statistically significant difference between all pairs. The vessel density in the POAG group was 8.25% and 11.7% lower compared to the NTG and healthy groups, respectively; while the mean difference was less (2.97%) for the NTG and healthy group. In the POAG group, 67.2% of the variation in RPC can be explained by a model containing CDR and RNFL thickness, and in normal eyes 38.8% of the changes using a model containing RNFL. CONCLUSION: The peripapillary vessel density is reduced in both types of glaucoma. The vessel density in NTG was significantly lower than in the healthy eyes, despite the lack of significant difference in RNFL thickness and neuroretinal rim area between them.

In vitro siRNA-mediated GPX4 and AKT1 silencing in oxaliplatin resistance cancer cells induces ferroptosis and apoptosis.

Oxaliplatin is a member of platinum-based chemotherapy drugs frequently used in colorectal cancer (CRC). However, resistance to oxaliplatin causes tumor progression and metastasis. Akt1 and Gpx4 are essential regulator genes of apoptosis and ferroptosis pathways. Inhibition of these genes might eradicate oxaliplatin resistance in resistant CRC cells. We compared two cell death strategies to reverse drug resistance in Caco-2 and HT-29 oxaliplatin-resistant cell lines. We used the AKT1-specific siRNA to induce apoptosis. Also, GPX4-specific siRNA and FIN56 were utilized to generate ferroptosis. The effect of these treatments was assessed by reactive oxygen species (ROS) formation, cell viability, and protein expression level assays. Besides, the expression of GPX4, CoQ10, and NRF2 was assessed in both cell lines after treatments. Correctly measuring the expression of these responsible genes and proteins confirms the occurrence of different types of cell death. In addition, the ability of Akt1/ GPX4 siRNA in resensitizing HT-29 and Caco-2 oxaliplatin resistance cells was evaluated. Our finding showed that the upregulation of GPX4/siRNA caused a reduction in GPX4 and CoQ10 expressions in both cell lines. However, the expression level of NRF2 showed the same level in our cell lines, so we observed a downregulation of NRF2 in resistant CRC cell lines. Cell viability assay indicated that induction of ferroptosis by GPX4/siRNA or FIN56 and apoptosis by Akt1/siRNA in resistant cell lines could reverse the oxaliplatin resistance. We concluded that downregulation of Akt1 or Gpx4 could increase the efficacy of oxaliplatin to overcome the resistance compared to FIN56.

Ferroptosis as a Potential Cell Death Mechanism Against Cisplatin-Resistant Lung Cancer Cell Line.

Purpose: Drug resistance is a challenging issue in cancer chemotherapy. Cell death induction is one of the main strategies to overcome chemotherapy resistance. Notably, ferroptosis has been considered a critical cell death mechanism in recent years. Accordingly, in this study, the different cell death strategies focused on ferroptosis have been utilized to overcome cisplatin resistance in an in vitro lung cancer model. Methods: The physiological functions of Akt1 and GPX4, as critical targets for ferroptosis and apoptosis induction, were suppressed by siRNA or antagonistic agents in resistant A549 cells. Afterward, the interventions' impacts on cell viability and reactive oxygen species (ROS) amount were analyzed by flow cytometry. Moreover, the alteration in the relevant gene and protein expression levels were quantified using Real-time PCR and western blot methods. Results: The result showed that the treatment with Akt1 siRNA reversed the cisplatin resistance in the A549 cell line through the induction of apoptosis. Likewise, the combination treatment of the GPX4 siRNA or FIN56 as ferroptosis inducers alongside cisplatin elevated ROS's cellular level, reduced the cellular antioxidant genes level and increased the cisplatin cytotoxic effect. Conclusion: In conclusion, our study indicated that ferroptosis induction can be considered a promising cell death strategy in cisplatin-resistant cancer cells.

Hyper-Branched Cationic Cyclodextrin Polymers for Improving Plasmid Transfection in 2D and 3D Spheroid Cells.

In this article, we used monolayer two dimensional (2D) and 3D multicellular spheroid models to improve our understanding of the gene delivery process of a new modified cationic hyper-branched cyclodextrin-based polymer (Ppoly)-loaded plasmid encoding Enhanced Green Fluorescent Protein (EGFP). A comparison between the cytotoxicity effect and transfection efficiency of the plasmid DNA (pDNA)-loaded Ppoly system in 2D and 3D spheroid cells determined that the transfection efficiency and cytotoxicity of Ppoly-pDNA nanocomplexes were lower in 3D spheroids than in 2D monolayer cells. Furthermore, histopathology visualization of Ppoly-pDNA complex cellular uptake in 3D spheroids demonstrated that Ppoly penetrated into the inner layers. This study indicated that the Ppoly, as a non-viral gene delivery system in complex with pDNA, is hemocompatible, non-toxic, high in encapsulation efficiency, and has good transfection efficiency in both 2D and 3D cell cultures compared to free pDNA and lipofectamine (as the control).

Targeted Codelivery of Prodigiosin and Simvastatin Using Smart BioMOF: Functionalization by Recombinant Anti-VEGFR1 scFv.

Biological metal-organic frameworks (BioMOFs) are hybrid compounds in which metal nodes are linked to biocompatible organic ligands and have potential for medical application. Herein, we developed a novel BioMOF modified with an anti-VEGFR1 scFv antibody (D16F7 scFv). Our BioMOF is co-loaded with a combination of an anticancer compound and a lipid-lowering drug to simultaneously suppress the proliferation, growth rate and metastases of cancer cells in cell culture model system. In particular, Prodigiosin (PG) and Simvastatin (SIM) were co-loaded into the newly synthesized Ca-Gly BioMOF nanoparticles coated with maltose and functionalized with a recombinant maltose binding protein-scFv fragment of anti-VEGFR1 (Ca-Gly-Maltose-D16F7). The nanoformulation, termed PG + SIM-NP-D16F7, has been shown to have strong active targeting behavior towards VEGFR1-overexpresing cancer cells. Moreover, the co-delivery of PG and SIM not only effectively inhibits the proliferation of cancer cells, but also prevents their invasion and metastasis. The PG + SIM-NP-D16F7 nanocarrier exhibited stronger cytotoxic and anti-metastatic effects compared to mono-treatment of free drugs and drug-loaded nanoparticles. Smart co-delivery of PG and SIM on BioMOF nanoparticles had synergistic effects on growth inhibition and prevented cancer cell metastasis. The present nanoplatform can be introduced as a promising tool for chemotherapy compared with mono-treatment and/or non-targeted formulations.

Mesenchymal Stem Cells and Cancer Stem Cells: An Overview of Tumor- Mesenchymal Stem Cell Interaction for Therapeutic Interventions.

Tumors are made up of different types of cancer cells that contribute to tumor heterogeneity. Among these cells, cancer stem cells (CSCs) have a significant role in the onset of cancer and development. Like other stem cells, CSCs are characterized by the capacity for differentiation and self-renewal. A specific population of CSCs is constituted by mesenchymal stem cells (MSCs) that differentiate into mesoderm-specific cells. The pro-or anti-tumorigenic potential of MSCs on the proliferation and development of tumor cells has been reported as contradictory results. Also, tumor progression is specified by the corresponding tumor cells like the tumor microenvironment. The tumor microenvironment consists of a network of reciprocal cell types such as endothelial cells, immune cells, MSCs, and fibroblasts as well as growth factors, chemokines, and cytokines. In this review, recent findings related to the tumor microenvironment and associated cell populations, homing of MSCs to tumor sites, and interaction of MSCs with tumor cells will be discussed.

The Effect of Length and Structure of Attached Polyethylene Glycol Chain on Hydrodynamic Radius, and Separation of PEGylated Human Serum Albumin by Chromatography.

Purpose: This study focuses on the effect of length and structure of attached polyethylene glycol (PEG) chain on hydrodynamic radius (Rh ) and chromatographic retention of PEGylated protein. To this aim human serum albumin (HSA) as a standard protein was PEGylated site specifically with mPEG-maleimide. Methods: Separated PEG_HSA fractions were analyzed by size exclusion and anion exchange chromatography (AExC). The purity of fractions and the relative mobility of PEGylated and native proteins were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Hydrodynamic radius was determined based on the retention time of fractions on size exclusion chromatography (SEC), and also according to the previously reported equations. Results: A linear relation was shown between the molecular weight of attached PEG and Rh of PEGylated HSA. No significant difference between Rh of proteins modified with linear and branched PEG was shown. In SDS-PAGE, the delaying effect of branched PEG on movement of PEGylated protein was higher than that of linear PEG. Conclusion: As PEGylated HSA and dimer HSA have almost the same size and in SEC they elute at very close retention times, so in this case ion exchange chromatography (IExC) is more effective than SEC in separation of PEGylated HSA. Branched PEG- HSA showed earlier elution on anion exchange chromatography compared to linear PEG-HSA, that this can explain the different shielding effect of various structures of attached PEGs. The smaller size of PEGylated HSA in compare to the sum of the hydrodynamic radiuses of native HSA and attached PEG could be as a result of shielded attachment of polymer around protein.

Mesenchymal Stem Cells cause Telomere Length Reduction of Molt-4 Cells via Caspase-3, BAD and P53 Apoptotic Pathway.

Mesenchymal stem cells (MSCs) as undifferentiated cells are specially considered in cell-based cancer therapy due to unique features such as multi-potency, pluripotency, and self-renewal. A multitude of cytokines secreted from MSCs are known to give such multifunctional attributes, but details of their role are yet to be unknown. In the present study, MSCs were cultured, characterized and co-cultured with Molt-4 cells as acute lymphoblastic leukemia cell line in a trans-well plate. Then, cultured Molt-4 alone and Molt-4 co-cultured with MSCs (10:1) were collected on day 7 and subjected to real time-PCR and Western blotting for gene and protein expression assessment, respectively. Ki-67/caspase-3 as well as telomere length were investigated by flow cytometry and real time-PCR, respectively. The results showed that MSCs caused significant decrease in telomere length as well as hTERT gene expression of Molt-4 cells. Also, gene and protein expression of BAD and P53 were significantly increased. Furthermore, the flow cytometry analysis indicated the decrease and increase of the Ki-67 and caspaspase-3 expression, respectively. It was concluded that MSCs co-cultured with Molt-4 cells could be involved in the promotion of Molt-4 cell apoptosis via caspase-3, BAD, and P53 expression. In addition, the decrease of telomere length is another effect of MSCs on Molt-4 leukemic cells.

Direct quantitative detection of host cell residual DNA in recombinant Filgrastim by qPCR.

Host cell residual DNA is considered as an impurity in recombinant biopharmaceuticals. This study aimed to develop a direct qPCR method to quantify E. Coli residual DNA in recombinant Filgrastim. The specific primers were designed to amplify E. Coli's 16S-rDNA genomic region, which encodes the 16S-rRNA. The developed qPCR method showed that the designed primer has specifically amplified the target genome without any secondary reaction. The designed primer was also able to amplify the target gene as a representative of residual DNA in the drug matrix. Results show that the amount of residual DNA in Filgrastim is undetectable.

In vitro evaluation of cytotoxic effects of di (2-ethylhexyl) phthalate (DEHP) produced by Bacillus velezensis strain RP137 isolated from Persian Gulf.

Phthalates are widely used in polymer science and have potential toxicity related to their chemical structures. However, lots of evidence indicate that phthalate derivatives are undoubtedly produced as secondary metabolites by organisms, including plants, animals, and microorganisms. In the present study, Bacillus velezensis strain RP137 was cultured under optimized conditions. Its biomass was extracted with ethyl acetate with one fraction showing cytotoxic properties. A pure compound was isolated from the active fraction using combined silica gel and LH20 size exclusion column chromatography. Structural evaluation including FT-IR, 1H NMR, 13C NMR, HR-MS and CHN analysis identified the purified compound as di(2-ethylhexyl)phthalate (DEHP) with the formula C24H38O4 and the molecular weight of 389.29 Da. The microorganism-derived (stereospecific) DEHP was strongly reduced the proliferation and induced cytotoxic effects on various eukaryotic cell lines in compare to the synthetic racemic mixture of the compound when assessed by MTT assay. Furthermore, crystal violet assay and morphological changes confirmed the cytotoxic effect of DEHP. Interestingly, non-malignant SV40-immortalized fibroblast cells were less affected by the purified DEHP. Further evaluation on the antibacterial activity of DEHP documented no effect toward Gram-positive (S. aureus) and Gram-negative (E. coli and P. aeruginosa) pathogens even at a high concentration of 100 µM. In conclusion, existence of DEHP as byproduct of microorganism's metabolism can seriously be considered as a warning to human health.

Combating Antimicrobial Resistance With New-To-Nature Lanthipeptides Created by Genetic Code Expansion.

Due to the rapid emergence of multi-resistant bacterial strains in recent decades, the commercially available effective antibiotics are becoming increasingly limited. On the other hand, widespread antimicrobial peptides (AMPs) such as the lantibiotic nisin has been used worldwide for more than 40 years without the appearance of significant bacterial resistance. Lantibiotics are ribosomally synthesized antimicrobials generated by posttranslational modifications. Their biotechnological production is of particular interest to redesign natural scaffolds improving their pharmaceutical properties, which has great potential for therapeutic use in human medicine and other areas. However, conventional protein engineering methods are limited to 20 canonical amino acids prescribed by the genetic code. Therefore, the expansion of the genetic code as the most advanced approach in Synthetic Biology allows the addition of new amino acid building blocks (non-canonical amino acids, ncAAs) during protein translation. We now have solid proof-of-principle evidence that bioexpression with these novel building blocks enabled lantibiotics with chemical properties transcending those produced by natural evolution. The unique scaffolds with novel structural and functional properties are the result of this bioengineering. Here we will critically examine and evaluate the use of the expanded genetic code and its alternatives in lantibiotics research over the last 7 years. We anticipate that Synthetic Biology, using engineered lantibiotics and even more complex scaffolds will be a promising tool to address an urgent problem of antibiotic resistance, especially in a class of multi-drug resistant microbes known as superbugs.

Optimization of Fermentation Conditions to Enhance Cytotoxic Metabolites Production by Bacillus velezensis Strain RP137 from the Persian Gulf.

BACKGROUND: Isolation, introduction and producing bioactive compounds from bacteria, especially marine bacteria, is an attractive research area. One of the main challenges of using these metabolites as drug and their industrialization is the optimization of production conditions. METHODS: In the present study, the response surface methodology was applied to optimize the production of a cytotoxic extract (C-137-R) by Bacillus velezensis (B. velezensis) strain RP137. Initially, among the three carbon and three nitrogen sources, rice starch and potassium nitrate were selected as the best, with cell toxicity equal to IC50=54.4 and 45.1 µg/ml in human lung and liver cancer cell lines, respectively (A549 and HepG2). In the next step, fractional factorial design was performed to survey effect of seven physical and chemical factors on the amount of production, and the most important factors including carbon and nitrogen sources with the positive effect and the sea salt with negative effect were determined. Finally, using the central composite design with 20 experiments, the best concentrations of rice starch and potassium nitrate (1.5%) and sea salt (1%) were obtained. RESULTS: The average amount of dried extract produced in the optimum conditions was 131.1 mg/L and the best response was 71.45%, which is more than 28-fold better than the pre-optimized conditions. CONCLUSION: In general, it can be suggested that the use of modern statistical methods to optimize environmental conditions affecting the growth and metabolism of bacteria can be a highly valuable tool in industrializing the production of bioactive compounds.

Evaluation of the Bioactive Potential of Secondary Metabolites Produced by a New Marine Micrococcus Species Isolated from the Persian Gulf.

BACKGROUND: In the present work, a newly isolated marine bacterium, Micrococcus sp. MP76, from coastal area of Persian Gulf around Bushehr province, Iran, was identified with the ability to produce bioactive compounds. METHODS: The pigment production was optimized by changing carbon and nitrogen sources in bacterial growth media at 28°C and 220 rpm for 5 days. Partial purification of the pigment was carried out using suitable solvents. RESULTS: Maximum pigment extract was achieved (1.4 g/l) when cultured in the medium containing 0.5% (v/v) molasses, 0.5% (w/v) peptone, 1% (w/v) sea salt, 0.01% (w/v) potassium phosphate, and 0.05% (w/v) yeast extract, pH=7.0. Antibacterial effect assessment of the extract against pathogenic bacteria revealed the MIC values in the range of 4.2-7.5 mg/ml depending on different pathogens. The pigment extracted from medium supplemented by molasses and ammonium sulfate had 81% radical scavenging activity, and its IC50 value was 0.28 mg/ml. CONCLUSION: The newly isolated strain of Micrococcus genus from the Persian Gulf revealed a valuable source to access worth medicinal ingredients when cultured under optimized conditions.

Microindoline 581, an Indole Derivative from Microbacterium Sp. RP581 as A Novel Selective Antineoplastic Agent to Combat Hepatic Cancer Cells: Production, Optimization and Structural Elucidation.

Screening of bioactive compounds with potential binding affinity to DNA as one of the target molecules in fighting against cancer cells has gained the attention of many scientists. Finding such compounds in the cellular content of microorganisms, especially marine bacteria as valuable and rich natural resources, is of great importance. Microbacterium sp. RP581, as a member of Actinobacteria phylum, was isolated from the Persian Gulf coastal area and the production of the target compound was optimized using statistical methods in cheap culture ingredients. The purification of the target compound was performed by flash chromatography and preparative HPLC. Both molecular and structural analyses indicated that the compound was an indole derivate which was tentatively named as Microindoline 581. Interaction of Microindoline 581 with genomic and circular DNA revealed that this compound can cause double- strand breaks through binding to the DNA. The analysis of cellular growth and proliferation of various cancer cell lines suggested proper and specific effect of the Microindoline 581 towards HepG2 cells with an IC50 of 172.2 ± 1.7 µM. Additional studies on cell migration inhibition and cell-death induction indicated a concentration-dependent inhibitory effect on proliferation and induction of death of HepG2 cells. The selective action of Microindoline 581 which was isolated from the Microbacterium sp. RP581 in killing HepG2 cells might be due to its specific metabolism in those cells as a precursor.

A gene-based anti-angiogenesis therapy as a novel strategy for cancer treatment.

Angiogenesis-targeted therapy of cancer is considered a promising strategy for therapeutic management of cancer progression. Over the last two decades, a few anti-angiogenesis monoclonal antibodies (mAbs) blocking VEGF signaling have been developed and approved by the FDA. The most widely used anti-angiogenesis drug is bevacizumab which binds VEGFA and prevents its interaction with VEGF receptor leading to suppression of angiogenesis. Despite the remarkable success in development of angiogenesis inhibitory mAbs, their clinical application is limited by the high-cost of mAbs-based regimen which includes multiple doses of mAbs due to their short biological half-life. Antibody gene therapy is an alternative system of antibody production. In this study, we have developed a gene-based anti-VEGF mAb system which is expected to produce a high concentration of anti-VEGFA mAb upon a single administration in cancer patients. The full-length cDNA bevacizumab light and heavy chains joint with T2A sequence were cloned in pCDH lentivirus vector. The lentiviral particles expressing bevacizumab was produced in HEK-293T cells. Recombinant lentiviral particles containing bevacizumab (rLV-bev) efficiently transduced HEK-293cells and produced functional bevacizumab mAb. Bevacizumab expression in the transduced cell was assessed by qRT-PCR and western blot at both the mRNA and protein level, respectively. The functionality of the recombinant bevacizumab was confirmed using the tube formation assay in the co-culture system of endothelial cells and HT-29cells transduced with rLV-bev viral particles. Our results show that rLV-bev gene therapy can be useful for angiogenesis-targeted therapy of cancer.

Impact of Cultivation Condition and Media Content onChlorella vulgaris Composition.

Microalgae are a source material in food, pharmacy, and cosmetics industries for producing various products including high-protein nutritional supplements, synthetic pharmaceuticals, and natural colors. A promising algal source for such productions is Chlorella vulgaris which contains a considerable protein content. Similar to other microalgae, its desirability is minimal nutrient requirements since they are unicellular, photosynthetic, and fast-growing microorganisms. Another propitious option to be produced by C. vulgaris is biodiesel, since it is rich in oil too. Besides, algal well thriving in presence of increased amount of carbon dioxide makes them a practicable alternative biofuel resource without some problems of the traditional ones. At the same time, C. vulgaris is also a promising source for nutraceuticals such as amino acids, vitamins, and antioxidants. This review aims to discuss the conditions need to be observed for achieving a favorable growth efficiency of the C. vulgaris, as well as targeted productions such as biomass, antioxidant, and biofuel. Additionally, different approaches to induce any specific production are also considered comprehensively.

An Aminoglycoside Antibacterial Substance, S-137-R, Produced by Newly Isolated Bacillus velezensis Strain RP137 from the Persian Gulf.

Given antibiotic resistance in pathogens, finding antibiotics from new sources is always a topic of interest to scientists. In the present study, among various isolates from the Persian Gulf coastal area, the strain RP137 was selected as producer of antibacterial compound. Morphological and biochemical studies along with 16S rDNA sequencing showed that strain RP137 belongs to Bacillus genus and was tentatively named Bacillus velezensis strain RP137. The effect of various carbon and nitrogen sources on optimizing the production of antibacterial compound showed that the low-cost rice starch and potassium nitrate supply to the strain RP137 caused producing of 86.0 ± 8.7 µg/mL extract having the antibacterial activity. The fractionation of the primary methanol extract in different solvents followed by reversed-phase HPLC obtained a pure antibacterial-active sample, S-137-R. Structural analysis of the purified S-137-R with the help of FTIR, HR-MS, 1H-NMR, and 13C-NMR showed that the S-137-R compound is classified as aminoglycoside. Minimum inhibition concentration (MIC) of the pure compound for Gram-positive bacteria, Staphylococcus aureus and methicillin resistant Staphylococcus aureus, showed an average antibacterial effect of about 80 µg/mL and 150 µg/mL, respectively and for Pseudomonas aeruginosa (100 µg/mL), while having very little toxic effect on E. coli. Moreover, low cytotoxicity effect of the S-137-R on cancerous and normal cells as well as the low intensity of the hemolysis of red blood cells in higher concentrations of S-137-R make it an ideal candidate for further structure-activity relationship assessments towards its medical applications.

Substituted effect on some water-soluble Mn(II) salen complexes: DNA binding, cytotoxicity, molecular docking, DFT studies and theoretical IR & UV studies.

Based on the importance of central metal complexes to interact with DNA, in this research focused on synthesis of some new water soluble Mn(II) complexes 1-4 which modified substituted in ligand at the same position with N, Me, H, and Cl. These complexes were isolated and characterized by elemental analyses, FT-IR, electrospray ionization mass spectrometry (ESI-MS) and UV-vis spectroscopy. DNA binding studies had been studied by using circular dichroism (CD) spectroscopy, UV-vis absorption spectroscopy, cyclic voltammetry (CV), viscosity measurements, emission spectroscopy and gel electrophoresis which proposed the metal buildings go about as effective DNA binders were studied in the presence of Fish-DNA (FS-DNA) which showed the highest binding affinity to DNA with hydrophobic and electron donating substituent. Cell toxicity assays against two human leukemia (Jurkat) and breast cancer (MCF-7) cell lines showed that the complex 3 exhibited a remarkable effects equal to a famous anticancer drug, cisplatin that high cytotoxic activity strongly depend on the hydrophobic substituted ligand. In the theoretical part, density functional theory (DFT) was performed to optimize the geometry of complexes through IR and UV spectra of the complexes that ligand substitution did not affect the geometry and theoretical IR and UV spectra showed good resemblance to the experimental data. The docking studies calculated the lowest-energy between complexes and DNA with the minor grooves mode.