Novel 5-oxo-hexahydroquinoline derivatives: design, synthesis, in vitro P-glycoprotein-mediated multidrug resistance reversal profile and molecular dynamics simulation study

Overexpression of the efflux pump P-glycoprotein (P-gp) is one of the important mechanisms of multidrug resistance (MDR) in many tumor cells. In this study, 26 novel 5-oxo-hexahydroquinoline derivatives containing different nitrophenyl moieties at C-4 and various carboxamide substituents at C-3 were designed, synthesized and evaluated for their ability to inhibit P-gp by measuring the amount of rhodamine 123 (Rh123) accumulation in uterine sarcoma cells that overexpress P-gp (MES-SA/Dx5) using flow cytometry. The effect of compounds with highest MDR reversal activities was further evaluated by measuring the alterations of MES-SA/Dx5 cells' sensitivity to doxorubicin (DXR) using MTT assay. The results of both biological assays indicated that compounds bearing 2-nitrophenyl at C-4 position and compounds with 4-chlorophenyl carboxamide at C-3 demonstrated the highest activities in resistant cells, while they were devoid of any effect in parental nonresistant MES-SA cells. One of the active derivatives, 5c, significantly increased intracellular Rh123 at 100 mu M, and it also significantly reduced the IC50 of DXR by 70.1% and 88.7% at 10 and 25 mu M, respectively, in MES-SA/Dx5 cells. The toxicity of synthesized compounds against HEK293 as a noncancer cell line was also investigated. All tested derivatives except for 2c compound showed no cytotoxicity. A molecular dynamics simulation study was also performed to investigate the possible binding site of 5c in complex with human P-gp, which showed that this compound formed 11 average H-bonds with Ser909, Thr911, Arg547, Arg543 and Ser474 residues of P-gp. A good agreement was found between the results of the computational and experimental studies. The findings of this study show that some 5-oxo-hexahydroquinoline derivatives could serve as promising candidates for the discovery of new agents for P-gp-mediated MDR reversal

Seroepidemiology of rubella, measles, HBV, HCV and B19 virus within women in child bearing ages (Saravan City of Sistan and Bloochastan Province)

Present survey basically focused on women between 15-45 years of age resident in a town of Sistan and Baluchistan province named as Saravan city located in border of Pakistan-Iran in order to find out the seropositivity against the viruses in child bearing ages in the above stated under study community. This descriptive cross-sectional study was carried-out from 2001 up to 2002. Saravan town was divided into 4 geographical areas and each area was further sub-divided into 10 blocks and in each block 10 families were chosen randomly. In the next step by referring to each family from the chosen married women with specified age i.e., 15-45 years, 5 mL blood was collected. Serum was then separated and stored at -20°C before the assay. ELISA kit was employed to detect anti B19, anti rubella, anti measles, anti HBV and anti HCV antibody. Furthermore during samples collection a questionnaire filled for each woman under study. This study showed that 89.6% of women understudy were seropositive against measles, rubella (96.2%), B19 (59.2%), HCV (0.8%) and HBV (19.8%), respectively. According to the results of no serious problem with rubella in this area; But, about measles, the present immunity against measles in this area is insufficient. It seems that incidence of B19 infection in this region is same as other places in Iran. The rate of seropositivity against HBV and HCV indicated of these viruses circulating in the population in this area. © 2007 Academic Journals

Study of the effect of bacterial lipopolysaccharide on the structure and dynamics on mouse tubulin polymerization

Background and aims: In recent decades, there has been much research on the microtubule dynamics as well as on factors affecting it. According to different studies, lipopolysaccharide (LPS) is thought to play an indirect role in neurodegenerative diseases through enzymatic pathways which hyperphosphorylate Tau protein and dissociate it from microtubules. In the present study, it was aimed to assess the direct effect of LPS on the structure and dynamics of tubulin polymerization in vitro. Methods: In this study, mouse tubulins were purified through two cycles of temperature-dependent polymerization-depolymerization. Cellulose-phosphate chromatography was used to further purify tubulins. SDS-PAGE was used to analyze the purity of the tubulins. Circular dichroism (CD), intrinsic fluorescence and turbidity assays were used to assess the changes in secondary and tertiary structures, and the dynamics of tubulin polymerization in the presence of different concentrations of LPS (5pM, 5nM, 50nM, 0.5µM and 5µM), respectively. Results: SDS-PAGE analysis confirmed the purity of tubulins. The intrinsic fluorescence analysis and CD assay revealed the changes in the secondary and tertiary structures of tubulins in the presence of LPS. The results of turbidity assay indicated that LPS could reduce the polymerization of tubulins. Conclusion: Our results indicate that LPS is able to change the secondary and tertiary structures of tubulin and decreases tubulin polymerization. According to our results, lipopolysaccharide in addition to an indirect effect on the microtubules stability, as well as by decreases in tubulin polymerization could result in neurodegenerative diseases specially Alzheimer's diseases

The Effects of Functional Therapy on Motor Development in Children with Cerebral Palsy

ObjectivesThe cause of rheumatoid arthritis (RA) as a chronic inflammatory autoimmune disease is still unknown. It appears that both genetic and environmental factors play a role in its pathogenesis. Recent studies reveal that in addition to the CNS, immune cells synthesis neurotransmitters so that these catecholamines can regulate immune functions. The aim of this study is to evaluate the dopamine receptor gene expression profiles on peripheral blood mononuclear cells of rheumatoid arthritis patients in comparison with normal individuals.Material & MethodsIn the present study, we investigated dopamine receptor gene expression in PBMCs of 40 RA patients and 40 healthy individuals using Real Time-PCR.The specificities of the obtained Real time PCR products for the respective dopamine receptors fragments were confirmed by sequenced analysis capillary systemResultsWe found that DRD1-DRD5 types of dopamine receptors genes expression profiles of rheumatoid arthritis patients differ compared to healthy individuals. Moreover, a significant difference of DR2 and DR4 gene expression was seen in rheumatoid arthritis patients.ConclusionThis study showed that some types of dopamine receptors genes expression profiles alter in rheumatoid arthritis patients with comparison to healthy individuals Moreover, this alteration possibly could result in dysfunction of dopaminergic system in immune cells and finally lead to rheumatoid arthritis

Stress Transmission in a Granular System

A sample of soil under external loads shows nonlinear behaviour. These external loads are propagated through grain-to-grain contacts. Consequently, the grains are being subjected to both tensile and compressive stresses according to their shape, position, and number of contacts. Thus, the nonlinear mechanical behaviour of soil may be described by investigating inter-particle stress transmission. The direct measurement of stress is a challenging task, both experimentally and numerically. In this study, stress-transmitting grains in a sand specimen are identified using an image-based approach. The methodology consists of measuring the geometrical data of the individual grains and following their evolution. On the numerical side, a more realistic description of soil behaviour is provided by developing a computational approach that quantifies internal stresses in each individual grain, termed micro Finite Element (μFE) model. The fabric of a natural sand obtained from the micro computed tomography (μCT) is virtualised to simulate the mechanical response of the material. The grain-to-grain interactions under loading are modelled in a framework of combined discrete-finite element method. Each individual grain is represented by a collection of nodes and elements and modelled as a continuum body that can deform according to a prescribed constitutive properties with appropriate friction contact conditions. The insights that can be gained into the stress transmission mechanisms and yield initiation within the grains are shown in a case study of an intact sand subjected to 1D compression. This includes stress and displacement field, inertia tensor, and active contact area. The contact behaviour used in the model is validated against existing theories for a single sphere and an assembly of spheres under triaxial loading. Then, single grain tests are conducted experimentally and numerically in order to better understand the influence of grain morphology on stress transmission. This study shows the strong dependency of contact behaviour on grain morphology. In addition, the effect of surface roughness is investigated showing the role of asperity abrasion under low normal loading. The evaluation of the μFE model has yielded results that compare well to experimental data obtained from a triaxial test in a μCT scanner. The stress field within each grain in the granular media is studied, contributing new insights beyond the commonly reported force chains. The ‘stress chain’ concept is considered as an alternative way to reflect grain breakage that may initiate on the weak force network and compromise the stability of the assembly. It is thus suggested that the ‘stress chain’ concept can be richer than ‘force chain’ and contains information about grain shape, mechanical properties and local fabric

Unraveling urban form and collision risk: The spatial distribution of traffic accidents in Zanjan, Iran

Official statistics demonstrate the role of traffic accidents in the increasing number of fa-talities, especially in emerging countries. In recent decades, the rate of deaths and injuries caused by traffic accidents in Iran, a rapidly growing economy in the Middle East, has risen significantly with respect to that of neighboring countries. The present study illustrates an exploratory spatial analysis’ framework aimed at identifying and ranking hazardous locations for traffic accidents in Zanjan, one of the most populous and dense cities in Iran. This framework quantifies the spatiotem-poral association among collisions, by comparing the results of different approaches (including Kernel Density Estimation (KDE), Natural Breaks Classification (NBC), and Knox test). Based on descriptive statistics, five distance classes (2–26, 27–57, 58–105, 106–192, and 193–364 meters) were tested when predicting location of the nearest collision within the same temporal unit. The empirical results of our work demonstrate that the largest roads and intersections in Zanjan had a significantly higher frequency of traffic accidents than the other locations. A comparative analysis of distance bandwidths indicates that the first (2–26 m) class concentrated the most intense level of spatiotem-poral association among traffic accidents. Prevention (or reduction) of traffic accidents may benefit from automatic identification and classification of the most risky locations in urban areas. Thanks to the larger availability of open-access datasets reporting the location and characteristics of car accidents in both advanced countries and emerging economies, our study demonstrates the potential of an integrated analysis of the level of spatiotemporal association in traffic collisions over metropolitan regions

Challenges toward Sustainability? Experiences and Approaches to Literary Tourism from Iran

Interdisciplinary narrative studies are of great importance in several disciplines, especially in the humanities and social sciences. Cultural tourism and its sub-disciplines, including the complex issue of ‘literary tourism’, is an interdisciplinary field of investigation, positioned in between geography and urban–rural studies. In Iran, this form of tourism has been neglected so far—with no distinction between urban and rural areas—despite a particularly rich literary heritage. The present study recognizes the challenge of literary tourism in Iran, delineating some possible actions to develop it as a future engine of economic growth, especially in rural districts. As a contribution to a refined comprehension of literary tourism development paths, a content analysis was run collecting views and textual data on literary tourism in Iran. The empirical results of this study indicate that the mentioned challenges can be classified into several main dimensions and a broader set of sub-themes. The possible actions responding to such challenges can be classified into more dimensions and a vast number of sub-themes. Actions reducing territorial disparities and fueling entrepreneurship in local communities are appropriate to stimulate the emergence (and, possibly, consolidation) of literary tourism districts in Iran, giving an original contribution to sustainable development especially—but not exclusively—in rural settlements

Factors underlying life quality in urban contexts: Evidence from an industrial city (arak, iran)

Cities play a vital role in local development providing a high education level, specialized jobs and advanced services. When assessing living conditions and wellbeing in cities, economic indicators alone are generally unable to evaluate the inherent complexity of the 'quality of life' issue in urban environments. With rapid urbanization, shortage of infrastructures and services emerged in metropolitan regions of developing countries, leading to disadvantaged settlements, urban poverty, lower citizens' satisfaction, and an overall decline in life quality. Based on these premises, the present study illustrates a subjective investigation of life quality in an emerging economy such as Iran, focusing on Arak, the fourth largest industrial pole of the country. Based on a literature review on quality of life in industrial cities of emerging economies, subjective indicators of citizens' satisfaction on living quality in Arak were identified and quantified using empirical results from a field survey. Results of our study show that the overall satisfaction for living quality in Arak is rather low, reaching the lowest rank in the issues of environmental sanitation and public transportation. Lack of investments in urban infrastructure justifies the low citizens' perception of life quality in Arak city. The paper concludes outlining the urgent need of homogeneous and comparable macro-and micro-data on multiple aspects of quality of life at both city-level and metropolitan-level in emerging economies

The Founder Effect? -FXIII Deficiency in Southeast Iran: A Molecular Study Report

Background: Congenital factor XIII (FXIII) deficiency is an extremely rare bleeding disorder (RBD) with different clinical coagulation disorders and great impacts on the perioperative patient outcome. Its prevalence in Southeast Iran is approximately 4,000 times higher than the worldwide prevalence, with Trp187Arg (c.559T> C as the only causative mutation of FXIIID there. We investigated the founder effect of rs1742924, rs4960181, rs3778360 and rs4142290 using haplotype analysis to define the genetic phenomenon in this geographic region. Materials and Methods: In a case-control study, 10 patients with FXIIID and 10 healthy individuals were assessed. Initially, Trp187Arg (c.559T> C) mutation was assessed in all study populations using a PCR-RFLP technique, then haplotype analysis was performed by assessing rs1742924, rs4960181, rs3778360 and rs4142290 polymorphisms. Data were analyzed using a two-proportion z-test. Results: All patients were homozygote for Trp187Arg (c.559T>C), and this mutation was not observed in any form of homozygote or heterozygote in the control group. Polymorphisms in rs1742924, rs4960181, and rs377836 were homozygote (TT, GG, GG, respectively) and T, G, and G alleles distribution in cases and controls with significant difference (P<0.001, P<0.001, and P=0.01 respectively). Rs4142290 polymorphism showed no significant difference between patients and controls (P=0.3). Two types of haplotypes were observed in the case group, and haplotype number 1* was observed among 90% of them, while not observed in the control group. Conclusion: It seems that founder effectors of haplotype number *1 have more antiquity versus other haplotypes, and probably founder effect is responsible for this high prevalence of FXIIID in the southeast of Iran

In vitro and in vivo anticancer effect of pH-responsive paclitaxel-loaded niosomes

In this study, paclitaxel (PTX)-loaded pH-responsive niosomes modified with ergosterol were developed. This new formulation was characterized in terms of size, morphology, encapsulation efficiency (EE), and in vitro release at pH 5.2 and 7.4. The in vitro efficacy of free PTX and niosome/PTX was assessed using MCF7, Hela, and HUVEC cell lines. In order to evaluate the in vivo efficacy of niosomal PTX in rats as compared to free PTX, the animals were intraperitoneally administered with 2.5 mg/kg and 5 mg/kg niosomal PTX for two weeks. Results showed that the pH-responsive niosomes had a nanometric size, spherical morphology, 77% EE, and pH-responsive release in pH 5.2 and 7.4. Compared with free PTX, we found markedly lower IC50s when cancer cells were treated for 48 h with niosomal PTX, which also showed high efficacy against human cancers derived from cervix and breast tumors. Moreover, niosomal PTX induced evident morphological changes in these cell lines. In vivo administration of free PTX at the dose of 2.5 mg/kg significantly increased serum biochemical parameters and liver lipid peroxidation in rats compared to the control rats. The situation was different when niosomal PTX was administered to the rats: the 5 mg/kg dosage of niosomal PTX significantly increased serum biochemical parameters, but the group treated with the 2.5 mg/kg dose of niosomal PTX showed fewer toxic effects than the group treated with free PTX at the same dosage. Overall, our results provide proof of concept for encapsulating PTX in niosomal formulation to enhance its therapeutic efficacy. [Figure not available: see fulltext.