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1.  Carotenoids from microalgae to block oxidative stress 
BioImpacts : BI  2017;7(1):1-3.
Reactive oxygen species (ROS) are produced under normal physiological conditions and involved in several cellular biochemical processes. Their external or endogenous overproduction induces a disruption of redox signaling and control known as oxidative stress. Under oxidative stress, the cell membrane structures, enzyme functions and gene expression are compromised leading to the pathogenesis of several chronic inflammatory diseases including the cardiovascular pathologies. Attempts to find new therapeutic molecules capable of blocking the oxidative stress are of crucial importance.
Owing to their anti-inflammatory and antioxidant properties, carotenoids have been proposed for the prevention and treatment of chronic diseases. In particular, microalgae carotenoids such as astaxanthin and lutein have shown promising results. Due to their protective action, these carotenoids could have a high potential to treat ROS-related pathologies. However, a better understanding of their biological mechanisms of action and the appropriate administration and uses of delivery systems are needed in the prevention and treatment of chronic pathologies.
doi:10.15171/bi.2017.01
PMCID: PMC5439384
Oxidative stress; Carotenoids; Reactive Oxygen Species; Microalgae
2.  Properties of macerated herbal oil 
BioImpacts : BI  2017;7(1):13-23.
Introduction: The addition of herbs into hot sesame oil could increase the oil-pulling efficiency of sesame oil. The aim of present study was to modify the proportion of herbs and sesame oil with the addition of other ingredients including menthol, camphor, and borneol and improve the medicinal properties and the scent of the oil.
Methods: Macerated herbal oil was prepared by heat extraction of five species of herbs (Zingiber cassumunar, Zingiber zerumbet, Plantago major Linn, Citrus hystrix, and Amomum biflorum) with hot sesame oil. The study was performed to evaluate the anti-oxidant, anti-inflammatory, and anti-bacterial properties of this macerated herbal oil.
Results: Macerated herbal oil was evaluated for antioxidant activity using DPPH and ABTS assays. It was shown that at dilution 1:2 in DMSO, the macerated herbal oil had DPPH and ABTS radical scavenging activities equal to 63% and 22%, respectively. Macerated herbal oil dilution 1:8 in DMSO demonstrated ferric reducing capacity equivalent to ascorbic acid (0.208 µM) and had reducing power equivalent to butylated hydroxytoluene (BHT) 7.41 µg/mL. MTT assay was performed using immortalized human mesenchymal stem cells (HMSCs) as a cell culture model. The result indicated that the cytotoxic concentration of the macerated herbal oil was ≥ 2.5 µL/mL in complete DMEM. Anti-inflammatory effects were evaluated using the nitrite assay and RT-PCR. It was found that the macerated herbal oil could inhibit nitrite accumulation in culture media. Change in the expression of COX-2, Nrf2, and NF-kB in RT-PCR confirmed the anti-inflammatory activity of the macerated herbal oil.
Conclusion: It could be concluded that the macerated herbal oil could inhibit nitrite accumulation in culture media, which might be the inhibitory effect of the macerated herbal oil on COX-2 or Nrf2, the downstream modulator of the COX-2 pathway. Further intensive studies are needed for the optimization before bringing this macerated herbal oil into clinical application.
doi:10.15171/bi.2017.03
PMCID: PMC5439385
Antibacterial; Anti-inflammatory; Antioxidant; HMSCs; Macerated herbal oil
3.  Genetic polymorphisms of multidrug and toxin extrusion proteins (MATE1 and MATE2) in South Indian population 
BioImpacts : BI  2017;7(1):25-30.
Introduction: Drug transporters are key determinants of pharmacokinetic and pharmacodynamic profiles of certain drugs. SLC47A1 (MATE1) and SLC47A2 (MATE2) are major efflux transporters involved in the hepatic and renal excretion of many cationic drugs including metformin. Our study was proposed to determine the normative frequencies of the single nucleotide polymorphisms (SNPs) rs2289669 and rs12943590 in the SLC47A1 and SLC47A2 genes, respectively, in South Indian population and also to compare those with those of the HapMap populations.
Methods: One hundred two unrelated healthy volunteers from South India were enrolled in the study. Genomic DNA was extracted by ‘phenol-chloroform extraction method’ from the peripheral blood leucocytes and genotyping was accomplished by real-time polymerase chain reaction using TaqMan SNP genotyping assay method.
Results: In contrast to other populations, the minor allele in SLC47A1 gene was found to be "G" with a frequency of 46.6% in South Indian population. The populations of Hans Chinese in Beijing (HCB) [P = 0.017] and Japanese in Tokyo (JPT) [P < 0.001] had significantly different genotype and allele frequencies (SNP rs2289669) compared to those of South Indian population. Similarly, in the SNP rs12943590 of SLC47A2 gene, the genotype and allele frequencies of South Indian population differed significantly from those of Yoruba in Ibadan, Nigeria (YRI) [P < 0.001] and Utah residents with Northern and Western European ancestry (CEU) [P = 0.005] populations.
Conclusion: Thus, the allele and genotype distributions of SLC47A1 and SLC47A2 gene polymorphisms were established in South Indian population and were found to be different from the frequencies of other ethnicities.
doi:10.15171/bi.2017.04
PMCID: PMC5439386
Drug transporters; MATE1; MATE2; Single nucleotide polymorphisms; SLC47A1; SLC47A2
4.  Common chemotherapeutic agents modulate fatty acid distribution in human hepatocellular carcinoma and colorectal cancer cells  
BioImpacts : BI  2017;7(1):31-39.
Introduction: Cancer cells are critically correlated with lipid molecules, particularly fatty acids, as structural blocks for membrane building, energy sources, and related signaling molecules. Therefore, cancer progression is in direct correlation with fatty acid metabolism. The aim of this study was to investigate the potential effects of common chemotherapeutic agents on the lipid metabolism of hepatocellular carcinoma (HCC) and colorectal cancer (CRC) cells, with a focus on alterations in cellular fatty acid contents.
Methods: Human HepG2 and SW480 cell lines as HCC and CRC cells were respectively cultured in RPMI-1640 medium supplemented with non-toxic doses of 5-fluorouracil and doxorubicin for 72 hours. Oil Red O dye was used to estimate intracellular lipid vacuole intensity. Fatty acid analysis of isolated membrane phospholipids and cytoplasmic triglycerides (TG) was performed by gas-liquid chromatography (GLC) technique.
Results: Oil red O staining represented significantly higher lipid accumulation and density in cancer cells after exposure to the chemotherapeutic agents as compared to non-treated control cells. Doxorubicin and 5-fluorouracil treatment promoted the channeling of saturated fatty acids (SFAs) from phospholipids to triglyceride pool in both HepG2 (+5.91% and +8.50%, P < 0.05, respectively) and SW480 (+37.41% and +5.73%, P < 0.05, respectively) cell lines. However, total polyunsaturated fatty acid content was inversely shifted from TG to phospholipid fraction after doxorubicin and 5-fluorouracil incubation of HepG2 (+58.89% and +29.13%, P < 0.05, respectively) and SW480 (+19.20% and +14.65%, P < 0.05, respectively) cells.
Conclusion: Our data showed that common chemotherapeutic agents of HCC and CRC can induce significant changes in cellular lipid accumulation and distribution of fatty acids through producing highly saturated and unsaturated lipid droplets and membrane lipids, respectively. These metabolic side effects may be associated with gastrointestinal cancers treatment failure.
doi:10.15171/bi.2017.05
PMCID: PMC5439387
Chemotherapy; Doxorubicin; Fatty acids; Fluorouracil; Lipid droplets
5.  Time dependency of morphological remodeling of endothelial cells in response to substrate stiffness 
BioImpacts : BI  2017;7(1):41-47.
Introduction: Substrate stiffness regulates cellular behavior as cells experience different stiffness values of tissues in the body. For example, endothelial cells (ECs) covering the inner layer of blood vessels are exposed to different stiffness values due to various pathologic and physiologic conditions. Despite numerous studies, cells by time span sense mechanical properties of the substrate, but the response is not well understood. We hypothesized that time is a major determinant influencing the behavior of cells seeded on substrates of varying stiffness.
Methods: We monitored cell spreading, internal structure, 3D topography, and the viability of ECs over 24 hours of culture on polydimethylsiloxane (PDMS) substrates with two different degrees of elastic modulus.
Results: Despite significant differences in cell spreading after cell seeding, cells showed a similar shape and internal structure after 24 hours of culture on both soft and stiff substrates. However, 3D topographical images confirmed existence of rich lamellipodia and filopodia around the cells cultured on stiffer PDMS substrates.
Conclusion: It was concluded that the response of ECs to the substrate stiffness was time dependent with initial enhanced cellular spreading and viability on stiffer substrates. Results can provide a better comprehension of cell mechanotransduction for tissue engineering applications.
doi:10.15171/bi.2017.06
PMCID: PMC5439388
3D topography; HUVECs; Morphology; Substrate stiffness; Time dependency
6.  Perspective highlights on biodegradable polymeric nanosystems for targeted therapy of solid tumors  
BioImpacts : BI  2017;7(1):49-57.
Introduction: Polymeric nanoparticles (NPs) formulated using biodegradable polymers offer great potential for development of de novo drug delivery systems (DDSs) capable of delivering a wide range of bioactive agents. They can be engineered as advanced multifunctional nanosystems (NSs) for simultaneous imaging and therapy known as theranostics or diapeutics.
Methods: A brief prospective is provided on biomedical importance and applications of biodegradable polymeric NSs through reviewing the recently published literature.
Results: Biodegradable polymeric NPs present unique characteristics, including: nanoscaled structures, high encapsulation capacity, biocompatibility with non-thrombogenic and non-immunogenic properties, and controlled-/sustained-release profile for lipophilic and hydrophilic drugs. Once administered in vivo, all classes of biodegradable polymers (i.e., synthetic, semi-synthetic, and natural polymers) are subjected to enzymatic degradation; and hence, transformation into byproducts that can be simply eliminated from the human body. Natural and semi-synthetic polymers have been shown to be highly stable, much safer, and offer a non-/less-toxic means for specific delivery of cargo drugs in comparison with synthetic polymers. Despite being biocompatible and enzymatically-degradable, there are some drawbacks associated with these polymers such as batch to batch variation, high production cost, structural complexity, lower bioadhesive potential, uncontrolled rate of hydration, and possibility of microbial spoilage. These pitfalls have bolded the importance of synthetic counterparts despite their somewhat toxicity.
Conclusion: Taken all, to minimize the inadvertent effects of these polymers and to engineer much safer NSs, it is necessary to devise biopolymers with desirable chemical and biochemical modification(s) and polyelectrolyte complex formation to improve their drug delivery capacity in vivo.
doi:10.15171/bi.2017.07
PMCID: PMC5439389
Biodegradable polymers; Synthetic and semi-synthetic polymers; Natural polymers; Targeted therapy; Advanced drug delivery systems
7.  Liquigroud technique: a new concept for enhancing dissolution rate of glibenclamide by combination of liquisolid and co-grinding technologies 
BioImpacts : BI  2017;7(1):5-12.
Introduction: The potential of combining liquisolid and co-grinding technologies (liquiground technique) was investigated to improve the dissolution rate of a water-insoluble agent (glibenclamide) with formulation-dependent bioavailability.
Methods: To this end, different formulations of liquisolid tablets with a wide variety of non-volatile solvents contained varied ratios of drug: solvent and dissimilar carriers were prepared, and then their release profiles were evaluated. Furthermore, the effect of size reduction by ball milling on the dissolution behavior of glibenclamide from liquisolid tablets was investigated. Any interaction between the drug and the excipient or crystallinity changes during formulation procedure was also examined using X-ray diffraction (XRD) and differential scanning calorimetry (DSC).
Results: The present study revealed that classic liquisolid technique did not significantly affect the drug dissolution profile as compared to the conventional tablets. Size reduction obtained by co-grinding of liquid medication was more effective than the implementation of liquisolid technique in enhancing the dissolution rate of glibenclamide. The XRD and DSC data displayed no formation of complex or any crystallinity changes in both formulations.
Conclusion: An enhanced dissolution rate of glibenclamide is achievable through the combination of liquisolid and co-grinding technologies.
doi:10.15171/bi.2017.02
PMCID: PMC5439390
Co-grinding; Dissolution rate; Glibenclamide; Liquiground; Liquisolid
8.  Pleiotropic cytotoxicity of VacA toxin in host cells and its impact on immunotherapy  
BioImpacts : BI  2017;7(1):59-71.
Introduction: In the recent decades, a number of studies have highlighted the importance of Helicobacter pylori in the initiation and development of peptic ulcer and gastric cancer. Some potential virulence factors (e.g., urease, CagA, VacA, BabA) are exploited by this microorganism, facilitating its persistence through evading human defense mechanisms. Among these toxins and enzymes, vacuolating toxin A (VacA) is of a great importance in the pathogenesis of H. pylori. VacA toxin shows different pattern of cytotoxicity through binding to different cell surface receptors in various cells.
Methods: To highlight attempts in treatment for H. pylori infection, here, we discussed the VacA potential as a candidate for development of vaccine and targeted immunotherapy. Furthermore, we reviewed the related literature to provide key insights on association of the genetic variants of VacA with the toxicity of the toxin in cells.
Results: A number of investigations on the receptor(s) binding of VacA toxin confirmed the pleiotropic nature of VacA that uses a unique mechanism for internalization through some membrane components such as lipid rafts and glycophosphatidylinositol (GPI)-anchored proteins (GPI-AP). Considering the high potency of VacA toxin in the clinical presentations in infection and assisting persistence and colonization of H. pylori, it is considered as one of the pivotal components in production vaccines and monoclonal antibodies (mAbs).
Conclusion: It is possible to generate mAbs with a considerable potential to convert into secretory immunoglobulins that could penetrate into the niche of H. pylori and inhibit its normal functionalities. Further, conjugation of H. pylori targeting Ab fragments with the toxic agents or drug delivery systems (DDSs) offers new generation of H. pylori treatments.
doi:10.15171/bi.2017.08
PMCID: PMC5439391
Helicobacter pylori; VacA; Cell receptor; Vaccine; Immunotherapy
9.  Debate on human aging and lifespan 
BioImpacts : BI  2017;7(3):135-137.
Summary
The issue of human lifespan has long been a matter of controversy among scientists. In spite of the recent claim by Dong et al that human lifespan is limited to 115 years, with the mounting improvements in biotechnology and scientific understanding of aging, we may be confident that aging will slow down over the course of the current century extending human longevity much longer than 115 years.
doi:10.15171/bi.2017.16
PMCID: PMC5684504
Lifespan; Futurists; Human aging; Mitochondrial damage; Nuclear DNA damage; Neuro-stem cells; Exosomal microRNAs; Futurists; Optimists; Realists
10.  The effect of cell penetrating peptides on transfection activity and cytotoxicity of polyallylamine 
BioImpacts : BI  2017;7(3):139-145.
Introduction: Cationic polymers have the potential to be modified to achieve an ideal gene vector lacking viral vector defects. The aim of the present study was to improve polyallylamine (PAA) transfection efficiency and to reduce cytotoxicity by incorporating of cell-penetrating peptides (CPPs).
Methods: To prepare the peptide-based polyplexes, PAA (15 kDa) was modified with 2 peptides (TAT and CyLoP-1) by covering the 0.5% and 1% of amines. Buffer capacity and DNA condensation ability of modified polymer, particle size and zeta potential of nanoparticles, cell viability, and transfection activity of vectors were evaluated.
Results: In low carrier to plasmid (C/P) weight ratios such as 0.5 and 1, the unmodified polymer was more capable to condense the DNA compared to the synthesized vectors. In C/P ratio of 2, the plasmid was fully condensed in all vectors. The size of polyplexes ranged from 195 to 240 nm. The zeta potential was almost as the same as PAA and varied from 25 to 27 mV. All polyplexes increased the buffer capacity compared to PAA. The transfection efficiency was improved compared to unmodified polymer especially in the vectors modified with 1% of TAT or CyLoP-1 peptides in C/P ratio of 2. The cytotoxicity of prepared vectors was less than PAA. In most ratios, the cytotoxicity of the CyLoP-1 modified samples was less than the TAT modified ones.
Conclusion: Modification of PAA with CPPs improved the transfection activity of vector.
doi:10.15171/bi.2017.17
PMCID: PMC5684505
Cell penetrating peptides; Polyallylamine; Polyplexes; Transfection
11.  Investigation of the binding mechanism and inhibition of bovine liver catalase by quercetin: Multi-spectroscopic and computational study 
BioImpacts : BI  2017;7(3):147-153.
Introduction: The study on the side effects of various drugs and compounds on enzymes is a main issue for monitoring the conformational and functional changes of them. Quercetin (3,5,7,3ʹ,4ʹ-pentahydroxyflavone, QUE), a polyphenolic flavonoid, widely found in fruits, vegetables and it is used as an ingredient in foods and beverages. The interaction of bovine liver catalase (BLC) with QUE has been studied in this research by using different spectroscopic methods.
Methods: In this work, the interaction of QUE with BLC was investigated using different spectroscopic methods including ultraviolet-visible (UV-vis) absorption, circular dichroism (CD) and fluorescence spectroscopy and molecular docking studies.
Results: Fluorescence data at different temperatures, synchronous fluorescence and CD studies revealed conformational changes in the BLC structure in the presence of different concentration of QUE. Also, the fluorescence quenching data showed that QUE can form a non-fluorescent complex with BLC and quench its intrinsic emission by a static process. The binding constant (Ka) for the interaction was 104, and the number of binding site was obtained ~1. The ∆H, ∆S and ∆G changes were obtained, indicating that hydrophobic interactions play a main role in the complex formation. In vitro kinetic studies revealed that QUE can inhibit BLC activity through non-competitive manner. Molecular docking study results were in good agreement with experimental data, confirming only one binding site on BLC for QUE at a cavity among the wrapping domain, threating arm and β-barrel.
Conclusion: Inhibition of BLC activity upon interaction with QUE demonstrated that in addition to their beneficial effects, they should not be overlooked for their side effects.
doi:10.15171/bi.2017.18
PMCID: PMC5684506
Bovine liver catalase; Flavonoid; Molecular docking; Non-competitive inhibition; Quercetin; Static quenching
12.  "Grafting-from" synthesis and characterization of poly (2-ethyl-2-oxazoline)-b-poly (benzyl L-glutamate) micellar nanoparticles for potential biomedical applications  
BioImpacts : BI  2017;7(3):155-166.
Introduction: Recent advances in the field of poly (2-oxazolines) as bio-inspired synthetic pseudopeptides have proven their potential biomedical applications such as drug delivery and tissue engineering.
Methods: In order to fabricate a biodegradable micellar nanoparticle of poly (2-ethyl 2-oxazoline)-b-poly (benzyl L-glutamate) or pEOx-b-pBLG, "grafting-from" synthesis approach was used involving consecutive steps of cationic ring-opening polymerization of 2-ethyl-2-oxazoline, amine functionalization of pEOx using 1-Boc-piperazine and N-carboxyanhydride polymerization of γ-benzyl- L-glutamate. Following hydrolysis of the copolymer, the protecting γ-benzyl groups were removed yielding a double-hydrophilic block ionomer of pEOx-b-poly (L-glutamic acid). The polymers were characterized by FTIR, 1H-NMR, size exclusion chromatography and differential scanning calorimetry (DSC). Aqueous assembly of the polymers was investigated by pyrene assay, dynamic light scattering, and transmission electron microscopy. MTT cytotoxicity assay was also performed to determine the cytocompatibility in various tumor cell lines.
Results: The polymeric micelles presented a uni-modal size distribution with mean hydrodynamic diameter of 149.8 ± 10.6 nm and critical aggregation concentration of 60 µg/mL. The average molecular weight of pEOx increased from ~ 14 to 20 kDa for pEOx-b-poly (L-glutamic acid) as determined by light scattering (Debye plot), indicating a successful copolymerization. MTT assay showed little to no practical cytotoxicity at concentrations below 1 mg/mL.
Conclusion: Multi-step synthesis of pEOx-b-pBLG and subsequent alkaline hydrolysis were performed to obtain the block ionomer pEOx-b-poly (L-glutamic acid). Both pEOx-based copolymers can be considered for various potential applications such as loading and delivery of drugs, genes, and contrast agents either by chemical conjugation or physical loading.
doi:10.15171/bi.2017.19
PMCID: PMC5684507
Grafting-from synthesis; Nano-assembly; Double hydrophilic block ionomer; Poly (2-oxazolines) functionalization; Ring-opening polymerization; Poly (L-glutamic acid)
13.  Thermoresponsive graphene oxide – starch micro/nanohydrogel composite as biocompatible drug delivery system 
BioImpacts : BI  2017;7(3):167-175.
Introduction: Stimuli-responsive hydrogels, which indicate a significant response to the environmental change (e.g., pH, temperature, light, …), have potential applications for tissue engineering, drug delivery systems, cell therapy, artificial muscles, biosensors, etc. Among the temperature-responsive materials, poly (N-isopropylacrylamide) (PNIPAAm) based hydrogels have been widely developed and their properties can be easily tailored by manipulating the properties of the hydrogel and the composite material. Graphene oxide (GO), as a multifunctional and biocompatible nanosheet, can efficiently improve the mechanical strength and response rate of PNIPAAm-based hydrogels. Here, hydrogel composites (HCs) of PNIPAAm with GO was developed using the modified starch as a biodegradable cross-linker.
Methods: Micro/nanohydrogel composites were synthesized by free radical polymerization of NIPAAm in the suspension of different feed ratio of GO using maleate-modified starch (St-MA) as cross-linker and Tetrakis (hydroxymethyl) phosphonium chloride (THPC) as a strong oxygen scavenger. The HCs were characterized by FT-IR, DSC, TGA, SEM, and DLS. Also, the phase transition, swelling/deswelling behavior, hemocompatibility and biocompatibility of the synthesized HCs were investigated.
Results: The thermal stability, phase transition temperature and internal network crosslinking of HCs increases with increasing of the GO feed ratio. Also, the swelling/deswelling, hemolysis, and MTT assays studies confirmed that the HCs are a fast response, hemocompatible and biocompatible materials.
Conclusion: The employed facile approach for the synthesis of HCs yields an intelligent material with great potential for biomedical applications.
doi:10.15171/bi.2017.20
PMCID: PMC5684508
Biocompatible; Hemolysis; Hydrogel composite; Swelling/deswelling; Thermoresponsive
14.  pH responsive cross-linked polymeric matrices based on natural polymers: effect of process variables on swelling characterization and drug delivery properties 
BioImpacts : BI  2017;7(3):177-192.
Introduction: The current work was aimed to design and synthesize novel crosslinked pH-sensitive gelatin/pectin (Ge/Pec) hydrogels using different polymeric ratios and to explore the effect of polymers and degree of crosslinking on dynamic, equilibrium swelling and in vitro release behavior of the model drug (Mannitol).
Methods: The Ge/Pec based hydrogels were prepared using glutaraldehyde as the crosslinker. Various structural parameters that affect their release behavior were determined, including swelling study, porosity, sol-gel analysis, average molecular weight between crosslinks (Mc), volume fraction of polymer (V2,s), solvent interaction parameter (χ) and diffusion coefficient. The synthesized hydrogels were subjected to various characterization tools like Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and DSC differential scanning calorimetry (DSC) and scanning electron microscopy (SEM).
Results:The hydrogels show highest water uptake and release at lower pH values. The FTIR spectra showed an interaction between Ge and Pec, and the drug-loaded samples also showed the drug-related peaks, indicating proper loading of the drug. DSC and TGA studies confirmed the thermal stability of hydrogel samples, while SEM showed the porous nature of hydrogels. The drug release followed non-Fickian diffusion or anomalous mechanism.
Conclusion: Aforementioned characterizations reveal the successful formation of copolymer hydrogels. The pH-sensitive swelling ability and drug release behavior suggest that the rate of polymer chain relaxation and drug diffusion from these hydrogels are comparable which also predicts their possible use for site-specific drug delivery.
doi:10.15171/bi.2017.21
PMCID: PMC5684509
Controlled delivery; Mannitol; Natural polymers; Stimuli responsive; Superabsorbent
15.  Lactobacillus plantarum induces apoptosis in oral cancer KB cells through upregulation of PTEN and downregulation of MAPK signalling pathways 
BioImpacts : BI  2017;7(3):193-198.
Introduction: The oral tumor is the sixth most prevalent type of cancer worldwide and the second leading cause of cancer-related mortality. Although chemotherapy and immunotherapy are the main strategies for the treatment of oral cancer, an emergence of inevitable resistance to these treatment modalities is the major drawback that causes recurrence of the disease. Nowadays, probiotics have been suggested as adjunctive and complementary treatment modalities for improving the impacts of chemotherapy and immunotherapy agents. Probiotics, the friendly microflora in our bodies, contribute to the production of useful metabolites with positive effects on the immune system against various diseases such as cancer.
Methods: Lactobacillus plantarum is one of the most important bacteria, which commensally live in the human oral system. In the current study, the impacts of L. plantarum on maintaining oral system health were investigated, and the molecular mechanisms of inhibition of oral cancer KB cells mediated by L. plantarum were evaluated using real-time polymerase chain reaction (PCR) and FACS flow cytometry analyses.
Results: Our findings showed that L. plantarum is effective in the signal transduction of the oral cancer cells through upregulation and downregulation of PTEN and MAPK pathways, respectively.
Conclusion: Based on the biological effects of oral candidate probiotics candidate bacterium L. plantarum on functional expression of PTEN and MAPK pathways, this microorganism seems to play a key role in controlling undesired cancer development in the oral system. Taken all, L. plantarum is proposed as a potential candidate for probiotics cancer therapy.
doi:10.15171/bi.2017.22
PMCID: PMC5684510
Cell signaling; MAPK; Oral cancer; Probiotics; PTEN; Cancer therapy
16.  Osmotic conditions could promote scFv antibody production in the Escherichia coli HB2151 
BioImpacts : BI  2017;7(3):199-206.
Introduction: Single chain variable fragment (scFv) antibodies are reduced forms of the whole antibodies that could be regarded as an alternative tool for diagnostic and therapeutic purposes. The optimization of processes and environmental conditions is necessary to increase the production yields and enhance the productivity. This can result in a cost-effective process and respond to the high demand for these antibodies.
Methods: In this research, physical and chemical factors influencing the batch fermentation was investigated in 50 mL batch tubes using minimum media to find the optimum conditions for production of a single chain variable fragment antibody in the Escherichia coli HB2151. Experimental designs were used to screen the effective parameters and to optimize the main factors.
Results: Arabinose was used instead of IPTG as a cheaper and nontoxic inducer and its optimum concentration was determined 0.1% (w/w). Induction duration time and filling volume fraction were set on the relatively better states 24 hours and 1/10 respectively. Regarding our previous study, stationary phase of the cell growth was selected as induction start time that showed higher specific scFv production yields (YP/X) in the minimum media. Finally, a statistical experimental design was extended to a central composite design (CCD) and analysis was performed based on sucrose and sorbitol concentrations producing osmotic condition for induction. The optimum region in the contour plot for the periplasmic scFv production was an osmotic circle area with total sugar molarity 0.8 to 0.9.
Conclusion: Sugars such as sucrose and sorbitol producing osmotic conditions could lead to periplasmic scFv concentrations up to 2.85 mg/L of culture media improving scFv concentration near to five times of the average of the screening step (0.59 mg/L).
doi:10.15171/bi.2017.23
PMCID: PMC5684511
Optimization; scFv; Inducer; Osmotic condition; Antibody; Escherichia coli
17.  CFD simulation of blood flow inside the corkscrew collaterals of the Buerger’s disease 
BioImpacts : BI  2016;6(1):41-47.
Introduction: Buerger’s disease is an occlusive arterial disease that occurs mainly in medium and small vessels. This disease is associated with Tobacco usage. The existence of corkscrew collateral is one of the established characteristics of the Buerger’s disease.
Methods: In this study, the computational fluid dynamics (CFD) simulation of blood flow within the corkscrew artery of the Buerger’s disease is conducted. The geometry of the artery is constructed based on the actual corkscrew artery of a patient diagnosed with the Buerger’s disease. The blood properties are the same as the actual blood properties of the patient. The blood flow rate is taken from the available experimental data in the literature.
Results: The local velocity patterns, pressure and kinematic viscosity distributions in different segments of the corkscrew collateral artery was demonstrated and discussed for the first time for this kind of artery. The effects of non-Newtonian consideration for the blood viscosity behavior were investigated in different segments of the artery. Moreover, the variations of the blood flow patterns along the artery were investigated in details for each segment.
Conclusion: It was found that the flow patterns were affected by the complex geometry of this artery in such a way that it could lead to the presence of sites that were prone to the accumulation of the flowing particles in blood like nicotine. Furthermore, due to the existence of many successive bends in this artery, the variations of kinematic viscosity along this artery were significant, therefore the non-Newtonian behavior of the blood viscosity must be considered.
doi:10.15171/bi.2016.06
PMCID: PMC4916545  PMID: 27340623
Blood flow patterns; Buerger’s disease; Corkscrew collateral; Non-Newtonian viscosity; Numerical modelling
18.  Applications of electrospinning/electrospraying in drug delivery 
BioImpacts : BI  2016;6(1):1-2.
During recent years, nanoscaled materials have gained much attention because of their applications in the field of pharmaceutical and biomedical sciences. Electrospinning/electrospraying, as simple, effective and single-step methods, are used in the preparation of nanostructured materials (nanofibers and nanobeads). They offer an opportunity for direct encapsulation of the different types of drug molecules. The generated nanomaterials possess high surface area with porous characteristics, and the liberation of the loaded drugs follows a controlled-release pattern. Because of their wide applications in medical/pharmaceutical researches, the aim of this editorial is to highlight the importance of electrospinning/electrospraying technologies in drug delivery.
doi:10.15171/bi.2016.08
PMCID: PMC4916546  PMID: 27340617
Drug delivery; Electrospinning; Electrospraying
19.  Foetal bovine serum-derived exosomes affect yield and phenotype of human cardiac progenitor cell culture 
BioImpacts : BI  2016;6(1):15-24.
Introduction: Cardiac progenitor cells (CPCs) represent a powerful tool in cardiac regenerative medicine. Pre-clinical studies suggest that most of the beneficial effects promoted by the injected cells are due to their paracrine activity exerted on endogenous cells and tissue. Exosomes are candidate mediators of this paracrine effects. According to their potential, many researchers have focused on characterizing exosomes derived from specific cell types, but, up until now, only few studies have analyzed the possible in vitro effects of bovine serum-derived exosomes on cell proliferation or differentiation.
Methods: The aim of this study was to analyse, from a qualitative and quantitative point of view, the in vitro effects of bovine serum exosomes on human CPCs cultured either as cardiospheres or as monolayers of cardiosphere-forming cells.
Results: Effects on proliferation, yield and molecular patterning were detected. We show, for the first time, that exogenous bovine exosomes support the proliferation and migration of human cardiosphere-forming cells, and that their depletion affects cardiospheres formation, in terms of size, yield and extra-cellular matrix production.
Conclusion: These results stress the importance of considering differential biological effects of exogenous cell culture supplements on the final phenotype of primary human cell cultures.
doi:10.15171/bi.2016.03
PMCID: PMC4916547  PMID: 27340620
Cardiac progenitor cells; Extra-cellular matrix; FBS-derived exosomes; Proliferation
20.  A microRNA isolation method from clinical samples 
BioImpacts : BI  2016;6(1):25-31.
Introduction: microRNAs (miRNAs) are considered to be novel molecular biomakers that could be exploited in the diagnosis and treatment of different diseases. The present study aimed to develop an efficient miRNA isolation method from different clinical specimens.
Methods: Total RNAs were isolated by Trizol reagent followed by precipitation of the large RNAs with potassium acetate (KCH3COOH), polyethylene glycol (PEG) 4000 and 6000, and lithium chloride (LiCl). Then, small RNAs were enriched and recovered from the supernatants by applying a combination of LiCl and ethanol. The efficiency of the method was evaluated through the quality, quantity, and integrity of the recovered RNAs using the A260/280 absorbance ratio, reverse transcription PCR (RT-PCR), and quantitative real-time PCR (q-PCR).
Results: Comparison of different RNA isolation methods based on the precipitation of DNA and large RNAs, high miRNA recovery and PCR efficiency revealed that applying potassium acetate with final precipitation of small RNAs using 2.5 M LiCl plus ethanol can provide high yield and quality small RNAs that can be exploited for clinical purposes.
Conclusion: The current isolation method can be applied for most clinical samples including cells, formalin-fixed and paraffin-embedded (FFPE) tissues and even body fluids with a wide applicability in molecular biology investigations.
doi:10.15171/bi.2016.04
PMCID: PMC4916548  PMID: 27340621
Clinical samples; FFPE tissues; microRNA isolation; Q-PCR
21.  Sulfasalazine-induced renal and hepatic injury in rats and the protective role of taurine 
BioImpacts : BI  2016;6(1):3-8.
Introduction: Sulfasalazine is a drug commonly administrated against inflammatory-based disorders. On the other hand, kidney and liver injury are serious adverse events accompanied by sulfasalazine administration. No specific therapeutic option is available against this complication. The current investigation was designed to evaluate the potential protective effects of taurine against sulfasalazine-induced kidney and liver injury in rats.
Methods: Male Sprague-Dawley rats were administered with sulfasalazine (600 mg/kg, oral) for 14 consecutive days. Animals received different doses of taurine (250, 500 and 1000 mg/ kg, i.p.) every day. Markers of organ injury were evaluated on day 15th, 24 h after the last dose of sulfasalazine.
Results: Sulfasalazine caused renal and hepatic injury as judged by an increase in serum level of creatinine (Cr), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP). The levels of reactive oxygen species (ROS) and lipid peroxidation were raised in kidney and liver of sulfasalazine-treated animals. Moreover, tissue glutathione reservoirs were depleted after sulfasalazine administration. Histopathological changes of kidney and liver also endorsed organ injury. Taurine administration (250, 500 and 1000 mg/kg/day, i.p) alleviated sulfasalazine-induced renal and hepatic damage.
Conclusion: Taurine administration could serve as a potential protective agent with therapeutic capabilities against sulfasalazine adverse effects.
doi:10.15171/bi.2016.01
PMCID: PMC4916549  PMID: 27340618
Anti-rheumatoid drugs; Drug-induced liver injury; Hepatotoxicity; Renal injury; Taurine
22.  Protective mechanisms of Cucumis sativus in diabetes-related modelsof oxidative stress and carbonyl stress  
BioImpacts : BI  2016;6(1):33-39.
Introduction: Oxidative stress and carbonyl stress have essential mediatory roles in the development of diabetes and its related complications through increasing free radicals production and impairing antioxidant defense systems. Different chemical and natural compounds have been suggested for decreasing such disorders associated with diabetes. The objectives of the present study were to investigate the protective effects of Cucumis sativus (C. sativus) fruit (cucumber) in oxidative and carbonyl stress models. These diabetes-related models with overproduction of reactive oxygen species (ROS) and reactive carbonyl species (RCS) simulate conditions observed in chronic hyperglycemia.
Methods: Cytotoxicity induced by cumene hydroperoxide (oxidative stress model) or glyoxal (carbonyl stress model) were measured and the protective effects of C. sativus were evaluated using freshly isolated rat hepatocytes.
Results: Aqueous extract of C. sativus fruit (40 μg/mL) prevented all cytotoxicity markers in both the oxidative and carbonyl stress models including cell lysis, ROS formation, membrane lipid peroxidation, depletion of glutathione, mitochondrial membrane potential decline, lysosomal labialization, and proteolysis. The extract also protected hepatocytes from protein carbonylation induced by glyoxal. Our results indicated that C. sativus is able to prevent oxidative stress and carbonyl stress in the isolated hepatocytes.
Conclusion: It can be concluded that C. sativus has protective effects in diabetes complications and can be considered a safe and suitable candidate for decreasing the oxidative stress and carbonyl stress that is typically observed in diabetes mellitus.
doi:10.15171/bi.2016.05
PMCID: PMC4916550  PMID: 27340622
C. sativus; Cucumber; Diabetes complications; Glycation; Hepatoprotection; Liver
23.  Advanced drug delivery and targeting technologies for the ocular diseases 
BioImpacts : BI  2016;6(1):49-67.
Introduction: Ocular targeted therapy has enormously been advanced by implementation of new methods of drug delivery and targeting using implantable drug delivery systems (DDSs) or devices (DDDs), stimuli-responsive advanced biomaterials, multimodal nanomedicines, cell therapy modalities and medical bioMEMs. These technologies tackle several ocular diseases such as inflammation-based diseases (e.g., scleritis, keratitis, uveitis, iritis, conjunctivitis, chorioretinitis, choroiditis, retinitis, retinochoroiditis), ocular hypertension and neuropathy, age-related macular degeneration and mucopolysaccharidosis (MPS) due to accumulation of glycosaminoglycans (GAGs). Such therapies appear to provide ultimate treatments, even though much more effective, yet biocompatible, noninvasive therapies are needed to control some disabling ocular diseases/disorders.
Methods: In the current study, we have reviewed and discussed recent advancements on ocular targeted therapies.
Results: On the ground that the pharmacokinetic and pharmacodynamic analyses of ophthalmic drugs need special techniques, most of ocular DDSs/devices developments have been designed to localized therapy within the eye. Application of advanced DDSs such as Subconjunctival insert/implants (e.g., latanoprost implant, Gamunex-C), episcleral implant (e.g., LX201), cationic emulsions (e.g., Cationorm™, Vekacia™, Cyclokat™), intac/punctal plug DDSs (latanoprost punctal plug delivery system, L-PPDS), and intravitreal implants (I-vitaion™, NT-501, NT- 503, MicroPump, Thethadur, IB-20089 Verisome™, Cortiject, DE-102, Retisert™, Iluvein™ and Ozurdex™) have significantly improved the treatment of ocular diseases. However, most of these DDSs/devices are applied invasively and even need surgical procedures. Of these, use of de novo technologies such as advanced stimuli-responsive nanomaterials, multimodal nanosystems (NSs)/nanoconjugates (NCs), biomacromolecualr scaffolds, and bioengineered cell therapies need to be further advanced to get better compliance and higher clinical impacts.
Conclusion: Despite mankind successful battle on ocular diseases, our challenge will continue to battle the ocular disease that happen with aging. Yet, we need to understand the molecular aspects of eye diseases in a holistic way and develop ultimate treatment protocols preferably as non-invasive systems.
doi:10.15171/bi.2016.07
PMCID: PMC4916551  PMID: 27340624
Eye diseases; Intraocular drug delivery; Ocular barriers; Ocular pharmacotherapy; Ophthalmic implants; Ocular drug targeting; Ophthalmology; Targeted therapy
24.  Improvement of mesenchymal stem cell differentiation into the endoderm lineage by four step sequential method in biocompatible biomaterial 
BioImpacts : BI  2016;6(1):9-13.
Introduction: The goal of the study described here, was to investigate the potential of umbilical cord derived mesenchymal stem cell (UC-MSCs) into hepatocyte like cells in a sequential 2D and 3D differentiation protocols as alternative therapy.
Methods: Mesenchymal stem cells (MSCs) were isolated from the umbilical cord (UC) and CD markers were analyzed by flow cytometry. For hepatic differentiation of UC-MSCs, cells were induced with a sequential 4-step protocol in 3D and 2D culture system. Urea concentration and albumin secretion into the culture medium was quantified by ELISA. Gene expression levels of AFP, ALB, and CK18 were determined by RT-PCR. Data were statistically analyzed by the SPSS software. The difference between the mean was considered significant when p < 0.05.
Results: Growth factor dependent morphological changes from elongated fibroblast-like cells to round epithelial cell morphology were observed in 2D culture. Cell proliferation analysis showed round-shaped morphology with clear cytoplasm and nucleus on the alginate scaffold in 3D culture. The mean valuses of albumin production and urea secretion were significantly higher in the 3D Culture system when compared with the 2D culture (p = 0.005 vs p = 0.001), respectively. Treatment of cells with TSA in the final step of differentiation induced an increased expression of CK18 and a decreased expression of αFP in both the 3D and 2D cultures (p = 0.026), but led to a decreased albumin gene expression, and an increased expression in the 2D culture (p = 0.001).
Conclusion: Findings of the present study indicated that sequential exposure of UC-MSCs with growth factors in 3D culture improves hepatic differentiation.
doi:10.15171/bi.2016.02
PMCID: PMC4916552  PMID: 27340619
3D culture; Liver; Mesenchymal stem cell; Umbilical cord
25.  Overexpression of molecular chaperons GRP78 and GRP94 in CD44hi/CD24lo breast cancer stem cells  
BioImpacts : BI  2016;6(2):105-110.
Introduction: Breast cancer stem cell with CD44hi/CD24lo phonotype is described having stem cell properties and represented as the main driving factor in breast cancer initiation, growth, metastasis and low response to anti-cancer agents. Glucoseregulated proteins (GRPs) are heat shock protein family chaperons that are charged with regulation of protein machinery and modulation of endoplasmic reticulum homeostasis whose important roles in stem cell development and invasion of various cancers have been demonstrated. Here, we investigated the expression levels of GRP78 and GRP94 in CD44hi/CD24lo phenotype breast cancer stem cells (BCSCs).
Methods: MCF7, T-47D and MDA-MB-231 breast cancer cell lines were used. CD44hi/CD24lo phenotype cell population were analyzed and sorted by fluorescence-activated cell sorting (FACS). Transcriptional and translational expression of GRP78 and GRP94 were investigated by western blotting and quantitative real time PCR.
Results: Results showed different proportion of CD44hi/CD24lo phenotype cell population in their original bulk cells. The ranking of the cell lines in terms of CD44hi/CD24lo phenotype cell population was as MCF7
Conclusion: Our results show a relationship between overexpression of GRP78 and GRP94 and exhibiting CD44hi/CD24lo phenotype in breast cancer cells. We conclude that upregulation of GRPs may be an important factor in the emergence of CD44hi/CD24lo phenotype BCSCs features.
doi:10.15171/bi.2016.15
PMCID: PMC4981248  PMID: 27525228
Breast cancer; Cancer stem cell; GRP78; GRP94; Overexpression

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