Search results for: fetal toxicity

Authors: Caroline M. Spagnol, Vera L. B. Isaac, Marcos A. Corrêa, Hérida R. N. Salgado

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Phenolic compounds are abundant in the Brazilian plant kingdom and they are part of a large and complex group of organic substances. Cinnamic acids are part of this group of organic compounds, and caffeic acid (CA) is one of its representatives. Antioxidants are compounds which act as free radical scavengers and, in other cases, such as metal chelators, both in the initiation stage and the propagation of oxidative process. The tyrosinase, polyphenol oxidase, is an enzyme that acts at various stages of melanin biosynthesis within the melanocytes and is considered a key molecule in this process. Some phenolic compounds exhibit inhibitory effects on melanogenesis by inhibiting the tyrosinase enzymatic activity and therefore has been the subject of studies. However, few studies have reported the effectiveness of these products and their safety. Objectives: To assess the inhibitory activity of tyrosinase, the antioxidant activity of CA and its cytotoxic potential. The method to evaluate the inhibitory activity of tyrosinase aims to assess the reduction transformation of L-dopa into dopaquinone reactions catalyzed by the enzyme. For evaluating the antioxidant activity was used the analytical methodology of DPPH radical inhibition. The cytotoxicity evaluation was carried out using the MTT method (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide), a colorimetric assay which determines the amount of insoluble violet crystals formed by the reduction of MTT in the mitochondria of living cells. Based on the results obtained during the study, CA has low activity as a depigmenting agent. However, it is a more potent antioxidant than ascorbic acid (AA), since a lower amount of CA is sufficient to inhibit 50% of DPPH radical. The results are promising since CA concentration that promoted 50% toxicity in HepG2 cells (IC50=781.8 μg/mL) is approximately 330 to 400 times greater than the concentration required to inhibit 50% of DPPH (IC50 DPPH= 2.39 μg/mL) and ABTS (IC50 ABTS= 1.96 μg/mL) radicals scavenging activity, respectively. The maximum concentration of caffeic acid tested (1140 mg /mL) did not reach 50% of cell death in HaCat cells. Thus, it was concluded that the caffeic acid does not cause toxicity in HepG2 and HaCat cells in the concentrations required to promote antioxidant activity in vitro, and it can be applied in topical products.

Keywords: caffeic acid, antioxidant, cytotoxicity, cosmetic

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Authors: Ankush Kalra, Mirza Masroor, Usha Manaktala, B. C. Koner, T. K. Mishra

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Introduction: Pre-eclampsia affects 3-5% of pregnancies worldwide and increases maternal-fetal morbidity and mortality. Reduced placental perfusion induces the release of biomolecules by the placenta into maternal circulation causing endothelial dysfunction. Zinc dependent matrix metalloproteinase-2 (MMP-2) may be up-regulated and interact with circulating factors of oxidative stress and inflammation to produce endothelial dysfunction in pre-eclampsia. Aim: To study the functional genetic polymorphism of MMP-2 gene (g-1306 C>T) in pre-eclampsia and its effect on serum MMP-2 levels in these patients. Method: Hundred pre-eclampsia patients and hundred age and gestation period matched healthy pregnant women with their consent were recruited in the study. Serum MMP-2 levels in all subjects were estimated using standard ELISA kits. MMP-2 gene (g.- 1306 C>T) SNPs were genotyped using whole blood by ASO-PCR. Result: The pre-eclampsia patients had higher serum levels of MMP-2 compared to the healthy pregnant (p < 0.05). Also the MMP-2 genotype was associated with significant alteration in the serum MMP-2 concentration in these patients (p < 0.05). Conclusion: This study results suggest an association of MMP-2 genetic polymorphism and serum levels of MMP-2 to the path physiology of hypertensive disorder of pregnancy.

Keywords: allele specific oligonucleotide polymerase chain reaction (ASO-PCR), enzyme linked immunosorbent assay (ELISA), matrix metalloproteinase-2 (MMP-2), pre-eclampsia

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Authors: Adela Diepoltova, Klara Konecna, Ondrej Jandourek, Petr Nachtigal

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A loss of control over antibiotic-resistant pathogens has become a global issue due to severe and often untreatable infections. This state is reflected in complicated treatment, health costs, and higher mortality. All these factors emphasize the urgent need for the discovery and development of new anti-infectives. One of the most common pathogens mentioned in the phenomenon of antibiotic resistance are bacteria of the genus Staphylococcus. These bacterial agents have developed several mechanisms against the effect of antibiotics. One of them is biofilm formation. In staphylococci, biofilms are associated with infections such as endocarditis, osteomyelitis, catheter-related bloodstream infections, etc. To author's best knowledge, no validated and standardized methodology evaluating candidate compound activity against staphylococcal biofilms exists. However, a variety of protocols for in vitro drug activity testing has been suggested, yet there are often fundamental differences. Based on our experience, a key methodological step that leads to credible results is to form a robust biofilm with appropriate attributes such as firm adherence to the substrate, a complex arrangement in layers, and the presence of extracellular polysaccharide matrix. At first, for the purpose of drug antibiofilm activity evaluation, the focus was put on various conditions (supplementation of cultivation media by human plasma/fetal bovine serum, shaking mode, the density of initial inoculum) that should lead to reproducible and robust in vitro staphylococcal biofilm formation in microtiter plate model. Three model staphylococcal reference strains were included in the study: Staphylococcus aureus (ATCC 29213), methicillin-resistant Staphylococcus aureus (ATCC 43300), and Staphylococcus epidermidis (ATCC 35983). The total biofilm biomass was quantified using the Christensen method with crystal violet, and results obtained from at least three independent experiments were statistically processed. Attention was also paid to the viability of the biofilm-forming staphylococcal cells and the presence of extracellular polysaccharide matrix. The conditions that led to robust biofilm biomass formation with attributes for biofilms mentioned above were then applied by introducing an alternative method analogous to the commercially available test system, the Calgary Biofilm Device. In this test system, biofilms are formed on pegs that are incorporated into the lid of the microtiter plate. This system provides several advantages (in situ detection and quantification of biofilm microbial cells that have retained their viability after drug exposure). Based on our preliminary studies, it was found that the attention to the peg surface and substrate on which the bacterial biofilms are formed should also be paid to. Therefore, further steps leading to the optimization were introduced. The surface of pegs was coated by human plasma, fetal bovine serum, and L-polylysine. Subsequently, the willingness of bacteria to adhere and form biofilm was monitored. In conclusion, suitable conditions were revealed, leading to the formation of reproducible, robust staphylococcal biofilms in vitro for the microtiter model and the system analogous to the Calgary biofilm device, as well. The robustness and typical slime texture could be detected visually. Likewise, an analysis by confocal laser scanning microscopy revealed a complex three-dimensional arrangement of biofilm forming organisms surrounded by an extracellular polysaccharide matrix.

Keywords: anti-biofilm drug activity screening, in vitro biofilm formation, microtiter plate model, the Calgary biofilm device, staphylococcal infections, substrate modification, surface coating

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Authors: Brahim Sow

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Background: Throughout West Africa, Balanites aegyptiaca (BA), or Zygophyllaceae, is widely used in traditional medicine to treat diabetes, hypertension, inflammation, malaria and liver disorders. In our recent research, we found that BA has nephroprotective potential against diabetes mellitus, hypertension and kidney disorders. However, to our knowledge, no systematic studies have been carried out on its derivative (toxicity) profile. Aim of the study: The study was conducted to assess the potential potency of the hydroalcoholic extract of BA bark in rats by the acute and sub-acute oral route. Materials and methods: Male and female rats in the acute depression study received BA extract orally at single doses of 500 mg/kg, 2000 mg/kg, 3000 mg/kg and 5000 mg/kg (n = 6 per group/sex). To assess acute depression, abnormal behaviour, toxic symptoms, weight and death were observed for 14 consecutive days. For the subacute impairment study, Wistar rats received the extract orally at doses of 125, 250 and 500 mg/kg (n=6 per group/sex) per day for 28 days. Behaviour and body weight were monitored daily. At the end of the treatment period, biochemical, haematological and histopathological examinations were performed, and gross and histopathological examinations of several organs were carried out. To determine the presence or absence of phytochemicals, the BA extract was subjected to gage phage chromatographic examination. Results: The absence of absorption chromatography of BA indicates the absence of cyanide groups. This suggests that the BA extract does not contain toxic substances. No mortality or adverse effects were observed at 5000 mg/kg in the acute depression test. With regard to body weight, general behaviour, relative organ weights, haematological and biochemical parameters, BA extract did not induce any mortality or potentially treatment-related effects in the sub-acute study. The normal architecture of the vital organs was revealed by histopathological examination, indicating the absence of morphological alterations. Conclusion: BA extract administered orally for 28 days at doses up to 500 mg/kg did not cause toxicological damage in rats in the present study. The median lethal dose (LD50) of the extract was estimated to be over 5000 mg/kg in an acute hyperglycaemia study.

Keywords: Balanites aegyptiaca L Delile, haematology, biochemistry, rat

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Authors: Kiran Datta, Daniella Holland-Hart, Anthony Byrne

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Introduction: Oesophago-gastric (OG) cancers are the fifth commonest in the UK, accounting for over 12,000 deaths each year. Most patients will present at later stages of the disease, with only 21% of patients with stage 4 disease surviving longer than a year. As a result, many patients are unsuitable for curative surgery and instead receive palliative treatment to improve prognosis and symptom burden. However, palliative chemotherapy can result in significant toxicity: almost half of the patients are unable to complete their chemotherapy regimen, with this proportion rising significantly in older and frailer patients. In addition, clinical trials often exclude older and frailer patients due to strict inclusion criteria, meaning there is limited evidence to guide which patients are most likely to benefit from palliative chemotherapy. Inappropriate chemotherapy administration is at odds with the goals of palliative treatment and care, which are to improve quality of life, and this also represents a significant resource expenditure. This literature review aimed to examine and appraise evidence regarding treatment resilience in order to guide clinicians in identifying the most suitable candidates for palliative chemotherapy. Factors influencing treatment resilience were assessed, as measured by completion rates, dose reductions, and toxicities. Methods: This literature review was conducted using rapid review methodology, utilising modified systematic methods. A literature search was performed across the MEDLINE, EMBASE, and Cochrane Library databases, with results limited to papers within the last 15 years and available in English. Key inclusion criteria included: 1) participants with either oesophageal, gastro-oesophageal junction, or gastric cancers; 2) patients treated with palliative chemotherapy; 3) available data evaluating the association between baseline participant characteristics and treatment resilience. Results: Of the 2326 papers returned, 11 reports of 10 studies were included in this review after excluding duplicates and irrelevant papers. Treatment resilience factors that were assessed included: age, performance status, frailty, inflammatory markers, and sarcopenia. Age was generally a poor predictor for how well patients would tolerate chemotherapy, while poor performance status was a better indicator of the need for dose reduction and treatment non-completion. Frailty was assessed across one cohort using multiple screening tools and was an effective marker of the risk of toxicity and the requirement for dose reduction. Inflammatory markers included lymphopenia and the Glasgow Prognostic Score, which assessed inflammation and hypoalbuminaemia. Although quick to obtain and interpret, these findings appeared less reliable due to the inclusion of patients treated with palliative radiotherapy. Sarcopenia and body composition were often associated with chemotherapy toxicity but not the rate of regimen completion. Conclusion: This review demonstrates that there are numerous measures that can estimate the ability of patients with oesophago-gastric cancer to tolerate palliative chemotherapy, and these should be incorporated into clinical assessments to promote personalised decision-making around treatment. Age should not be a barrier to receiving chemotherapy and older and frailer patients should be included in future clinical trials to better represent typical patients with oesophago-gastric cancers. Decisions regarding palliative treatment should be guided by these factors identified as well as patient preference.

Keywords: frailty, oesophago-gastric cancer, palliative chemotherapy, treatment resilience

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Authors: Kejal Joshi Reddy, Sirimavo Nair

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Micronutrient malnutrition affects pregnant women and children extremely with reference to growth manifestations in gestation as well as after birth. Early fetal development affected by iodine and iron deficiency leads to poor life quality. Various researchers have found interesting interrelations between iron and iodine. A few studies on impact assessment of DFS supplementation during pregnancy have been reported in India. Aim To provide meaningful contribution by assessing the efficacy of DFS supplementation on iodine and iron status of pregnant women. Design An interventional study. Setting A semi government hospital of urban Vadodara. Subjects Pregnant women (n=150) enrolled during first trimester (< 12 weeks) and followed up till the end of gestation, n=75 were divided in experimental (DFS supplemented) and control (Non supplemented) group. Results Impact on iron and iodine status was assessed by Hb concentration and UIE respectively. Mean Hb improved significantly (p < 0.001) (+0.42 g/dl) in experimental group and reduced non significantly (-0.20 g/dl) in control group at the end, since DFS provided additional 93 mg of iron within 6 months. Median UIE improved non significantly (278.6 to 299.01µg/L) in experimental group and decreased significantly (p < 0.05) (376.59 to 288.66 µg/L) in control group. Conclusion DFS could improve iron and iodine status of experimental group compared to control group. It is an effective measure to control two essential micronutrient deficiencies together.

Keywords: DFS supplementation, anemia, pregnancy, iodine deficiency, iron

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Authors: Vinaya Kambappa

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Propylphosphonic anhydride (T3P®)-DMSO is used as an efficient and mild reagent for the one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones from aromatic alcohols. Alcohols are oxidized in situ to aldehydes under mild conditions, which in turn undergo a three-component reaction with β-ketoester and urea/thiourea to afford 3,4-dihydropyrimidin-2(1H)-ones/thiones. The synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones directly from alcohols has been reported for the first time best to our knowledge, under mild reaction conditions in good yield. The easy work-up procedure, low cost and less toxicity of the reagent are the main advantages of this protocol.

Keywords: β-ketoester, propylphosphonic anhydride, three-component reaction, pyrimidine

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Authors: S. Besnaci, S. Bensoltane, H. Locif, S. Saadi

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To validate an ecotoxicological approach to assessing toxicological effects caused by the oxide powder of nano-iron Fe2O3, we searched in the ecotoxicology laboratory cell bodies bio accumulators and bio-indicators of soil pollution the snail Helix aspersa. In this study, we evaluated the toxicity of nano Fe2O3 during a very sensitive phase of development H.aspersa (embryonic stage). During embryonic development, we observed in treated with various concentrations of nano Fe2O3 (1.25 g/l, 1.5 g/l, and 2 g/l) compared to control, the deformation of the membrane of the egg and accumulation of this molecule at the rear of the egg proven by the photographs, as with the influence on the hatching percentage.

Keywords: eggs, embryotoxicity, Fe2O3, Helix aspersa, nanoparticles

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Authors: Fouzia Qamar, Shahida Hasnain

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The objective of the present study was to evaluate the possible role of Agrobacterium tumefaciens as a possible insect biocontrol agent. Pests selected for the present challenge were adult males of Periplaneta americana and last instar larvae of Pieris brassicae and Spodoptera litura. Different ranges of bacterial doses were selected and tested to score the mortalities of the insects after 24 hours, for the lethal dose estimation studies. Mode of application for the inoculation of the bacteria, was the microinjection technique. The evaluation of the possible entomopathogenic carrying attribute of bacterial Ti plasmid, led to the conclusion that the loss of plasmid was associated with the loss of virulence against target insects.

Keywords: agrobacterium tumefaciens, toxicity assessment, biopesticidal attribute, entomopathogenic agent

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Authors: Sanaz Alizadeh, Yves Comeau, Arshath Abdul Rahim, Sunhasis Ghoshal

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The application of silver nanoparticles (AgNPs) in personal care products, various household and industrial products has resulted in an inevitable environmental exposure of such engineered nanoparticles (ENPs). Ag ENPs, released via household and industrial wastes, reach water resource recovery facilities (WRRFs), yet the fate and transport of ENPs in WRRFs and their potential risk in the biological wastewater processes are poorly understood. Accordingly, our main objective was to elucidate the impact of long-term continuous exposure to AgNPs on biological activity of aerobic wastewater biofilm. The fate, transport and toxicity of 10 μg.L-1and 100 μg.L-1 PVP-stabilized AgNPs (50 nm) were evaluated in an attached growth biological treatment process, using lab-scale moving bed bioreactors (MBBRs). Two MBBR systems for organic matter removal were fed with a synthetic influent and operated at a hydraulic retention time (HRT) of 180 min and 60% volumetric filling ratio of Anox-K5 carriers with specific surface area of 800 m2/m3. Both reactors were operated for 85 days after reaching steady state conditions to develop a mature biofilm. The impact of AgNPs on the biological performance of the MBBRs was characterized over a period of 64 days in terms of the filtered biodegradable COD (SCOD) removal efficiency, the biofilm viability and key enzymatic activities (α-glucosidase and protease). The AgNPs were quantitatively characterized using single-particle inductively coupled plasma mass spectroscopy (spICP-MS), determining simultaneously the particle size distribution, particle concentration and dissolved silver content in influent, bioreactor and effluent samples. The generation of reactive oxygen species and the oxidative stress were assessed as the proposed toxicity mechanism of AgNPs. Results indicated that a low concentration of AgNPs (10 μg.L-1) did not significantly affect the SCOD removal efficiency whereas a significant reduction in treatment efficiency (37%) was observed at 100 μg.L-1AgNPs. Neither the viability nor the enzymatic activities of biofilm were affected at 10 μg.L-1AgNPs but a higher concentration of AgNPs induced cell membrane integrity damage resulting in 31% loss of viability and reduced α-glucosidase and protease enzymatic activities by 31% and 29%, respectively, over the 64-day exposure period. The elevated intercellular ROS in biofilm at a higher AgNPs concentration over time was consistent with a reduced biological biofilm performance, confirming the occurrence of a nanoparticle-induced oxidative stress in the heterotrophic biofilm. The spICP-MS analysis demonstrated a decrease in the nanoparticles concentration over the first 25 days, indicating a significant partitioning of AgNPs into the biofilm matrix in both reactors. The concentration of nanoparticles increased in effluent of both reactors after 25 days, however, indicating a decreased retention capacity of AgNPs in biofilm. The observed significant detachment of biofilm also contributed to a higher release of nanoparticles due to cell-wall destabilizing properties of AgNPs as an antimicrobial agent. The removal efficiency of PVP-AgNPs and the biofilm biological responses were a function of nanoparticle concentration and exposure time. This study contributes to a better understanding of the fate and behavior of AgNPs in biological wastewater processes, providing key information that can be used to predict the environmental risks of ENPs in aquatic ecosystems.

Keywords: biofilm, silver nanoparticle, single particle ICP-MS, toxicity, wastewater

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Authors: Junie B. Billones, Maria Constancia O. Carrillo, Voltaire G. Organo, Stephani Joy Y. Macalino, Inno A. Emnacen, Jamie Bernadette A. Sy

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The drug discovery and development process is generally known to be a very lengthy and labor-intensive process. Therefore, in order to be able to deliver prompt and effective responses to cure certain diseases, there is an urgent need to reduce the time and resources needed to design, develop, and optimize potential drugs. Computer-aided drug design (CADD) is able to alleviate this issue by applying computational power in order to streamline the whole drug discovery process, starting from target identification to lead optimization. This drug design approach can be predominantly applied to diseases that cause major public health concerns, such as tuberculosis. Hitherto, there has been no concrete cure for this disease, especially with the continuing emergence of drug resistant strains. In this study, CADD is employed for tuberculosis by first identifying a key enzyme in the mycobacterium’s metabolic pathway that would make a good drug target. One such potential target is the lipoate protein ligase B enzyme (LipB), which is a key enzyme in the M. tuberculosis metabolic pathway involved in the biosynthesis of the lipoic acid cofactor. Its expression is considerably up-regulated in patients with multi-drug resistant tuberculosis (MDR-TB) and it has no known back-up mechanism that can take over its function when inhibited, making it an extremely attractive target. Using cutting-edge computational methods, compounds from AnalytiCon Discovery Natural Derivatives database were screened and docked against the LipB enzyme in order to rank them based on their binding affinities. Compounds which have better binding affinities than LipB’s known inhibitor, decanoic acid, were subjected to in silico toxicity evaluation using the ADMET and TOPKAT protocols. Out of the 31,692 compounds in the database, 112 of these showed better binding energies than decanoic acid. Furthermore, 12 out of the 112 compounds showed highly promising ADMET and TOPKAT properties. Future studies involving in vitro or in vivo bioassays may be done to further confirm the therapeutic efficacy of these 12 compounds, which eventually may then lead to a novel class of anti-tuberculosis drugs.

Keywords: pharmacophore, molecular docking, lipoate protein ligase B (LipB), ADMET, TOPKAT

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Authors: Anelise Leal Vieira Cubas, Marina de Medeiros Machado, Marília de Medeiros Machado

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The volatile organic compounds - BTEX (Benzene, Toluene, Ethylbenzene, and Xylene) petroleum derivatives, have high rates of toxicity, which may carry consequences for human health, biota and environment. In this direction, this paper proposes a method of treatment of these compounds by using corona discharge plasma technology. The efficiency of the method was tested by analyzing samples of BTEX after going through a plasma reactor by gas chromatography method. The results show that the optimal residence time of the sample in the reactor was 8 minutes.

Keywords: BTEX, degradation, cold plasma, ecological sciences

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Authors: Chinnawat Satsananan

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The amount of heavy metals in our environment has been of great concern because of their toxicity when their concentration is more than the permissible level. These metals enter the environment by different ways such as industrial activities, soil pollution. We have used flame atomic absorption spectrometry technique for determination of the concentration of Co, Cd and Pb in different tissues of five samples of seafoods (mackerel, squid, mussels, scallops and shrimp). The concentrations of Co, Cd and Pb in all examined seafoods were less than the reported literature values (WHO). The results mentioned that the seafoods obtained from Thewet Market were safety to consumption and make the quality of life of people in the community look better.

Keywords: heavy metals, seafood, atomic absorption spectrometry, Bangkok

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Authors: I. Yunusa, M. A. Ibrahim, A. H. Yakasai, L. U. S. Ezeanyika

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This study was conducted to examine the level of heavy metals among 192 apparently healthy female adolescents randomly selected from three different boarding secondary schools in the urban area of the most populated city in north-western part of Nigeria. Atomic absorption spectrometry (AAS) was used to determine the plasma levels of the heavy metals which include cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), iron (Fe), manganese (Mn), molybdenum (Mo), nickel (Ni), lead (Pb) and zinc (Zn). Our findings revealed the following mean±SD values for each of the heavy metal; 0.11±0.01µg Cd/L, 0.09 ± 0.02µg Co/L, 0.19 ± 0.02 µg Cr/L, 0.91 ± 0.02 µg Cu/L, 1.53 ± 0.31 µg Fe/L, 0.01 ± 0.04 µg Mn/L, 0.3.8 ± 0.04µg Mo/L, 0.04±0.01µg Ni/L, 0.04 ± 0.01µg Pb/L and 2.80 ± 0.24µg Zn/L respectively. It was concluded that toxicity from heavy metals did not exist among female adolescents.

Keywords: heavy metals, female, adolescents, Nigeria

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Authors: Shokooh Moghadam, Mohammad Taghi Khorasani, Sajjad Seifi Mofarah, M. Daliri

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Through the recent two decades, the use of magnetic-property materials with the aim of target cell’s separation and eventually cancer treatment has incredibly increased. Numerous factors can alter the efficacy of this method on curing. In this project, the effect of magnetic field on adhesion of PDL and L929 cells on nanocomposite of iron oxide/PHB with different density of iron oxides (1%, 2.5%, 5%) has been studied. The nanocamposite mentioned includes a polymeric film of poly hydroxyl butyrate and γ-Fe2O3 particles with the average size of 25 nanometer dispersed in it and during this process, poly vinyl alcohol with 98% hydrolyzed and 78000 molecular weight was used as an emulsion to achieve uniform distribution. In order to get the homogenous film, the solution of PHB and iron oxide nanoparticles were put in a dry freezer and in liquid nitrogen, which resulted in a uniform porous scaffold and for removing porosities a 100◦C press was used. After the synthesis of a desirable nanocomposite film, many different tests were performed, First, the particles size and their distribution in the film were evaluated by transmission electron microscopy (TEM) and even FTIR analysis and DMTA test were run in order to observe and accredit the chemical connections and mechanical properties of nanocomposites respectively. By comparing the graphs of case and control samples, it was established that adding nano particles caused an increase in crystallization temperature and the more density of γ-Fe2O3 lead to more Tg (glass temperature). Furthermore, its dispersion range and dumping property of samples were raised up. Moreover, the toxicity, morphologic changes and adhesion of fibroblast and cancer cells were evaluated by a variety of tests. All samples were grown in different density and in contact with cells for 24 and 48 hours within the magnetic fields of 2×10^-3 Tesla. After 48 hours, the samples were photographed with an optic and SEM and no sign of toxicity was traced. The number of cancer cells in the case of sample group was fairly more than the control group. However, there are many gaps and unclear aspects to use magnetic field and their effects in cancer and all diseases treatments yet to be discovered, not to neglect that there have been prominent step on this way in these recent years and we hope this project can be at least a minimum movement in this issue.

Keywords: nanocomposite, cell attachment, magnetic field, cytotoxicity

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Authors: Syed Asif Hassan, Tabrej Khan

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Multiple sclerosis (MS) is a chronic demyelinating autoimmune disorder, of the central nervous system (CNS). In the present scenario, the current therapies either do not halt the progression of the disease or have side effects which limit the usage of current Disease Modifying Therapies (DMTs) for a longer period of time. Therefore, keeping the current treatment failure schema, we are focusing on screening novel analogues of the available DMTs that specifically bind and inhibit the Sphingosine1-phosphate receptor1 (S1PR1) thereby hindering the lymphocyte propagation toward CNS. The novel drug-like analogs molecule will decrease the frequency of relapses (recurrence of the symptoms associated with MS) with higher efficacy and lower toxicity to human system. In this study, an integrated approach involving ligand-based virtual screening protocol (Ultrafast Shape Recognition with CREDO Atom Types (USRCAT)) to identify the non-toxic drug like analogs of the approved DMTs were employed. The potency of the drug-like analog molecules to cross the Blood Brain Barrier (BBB) was estimated. Besides, molecular docking and simulation using Auto Dock Vina 1.1.2 and GOLD 3.01 were performed using the X-ray crystal structure of Mtb LprG protein to calculate the affinity and specificity of the analogs with the given LprG protein. The docking results were further confirmed by DSX (DrugScore eXtented), a robust program to evaluate the binding energy of ligands bound to the ligand binding domain of the Mtb LprG lipoprotein. The ligand, which has a higher hypothetical affinity, also has greater negative value. Further, the non-specific ligands were screened out using the structural filter proposed by Baell and Holloway. Based on the USRCAT, Lipinski’s values, toxicity and BBB analysis, the drug-like analogs of fingolimod and BG-12 showed that RTL and CHEMBL1771640, respectively are non-toxic and permeable to BBB. The successful docking and DSX analysis showed that RTL and CHEMBL1771640 could bind to the binding pocket of S1PR1 receptor protein of human with greater affinity than as compared to their parent compound (Fingolimod). In this study, we also found that all the drug-like analogs of the standard MS drugs passed the Bell and Holloway filter.

Keywords: antagonist, binding affinity, chemotherapeutics, drug-like, multiple sclerosis, S1PR1 receptor protein

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Authors: Ekta Yadav, Sukanta Bhattacharya, Brijesh Yadav, Ariel Hus, Jagjit Yadav

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Background and Significance: Respiratory exposure to toxicants (chemicals or particulates) causes disruption of lung homeostasis leading to lung toxicity/injury manifested as pulmonary inflammation, edema, and/or other effects depending on the type and extent of exposure. This emphasizes the need for investigating toxicant type-specific mechanisms to understand therapeutic targets. Aquaporins, aka water channels, are known to play a role in lung homeostasis. Particularly, the two major lung aquaporins AQP5 and AQP1 expressed in alveolar epithelial and vasculature endothelia respectively allow for movement of the fluid between the alveolar air space and the associated vasculature. In view of this, the current study is focused on understanding the regulation of lung aquaporins and other targets during inhalation exposure to toxic chemicals (Cigarette smoke chemicals) versus toxic particles (Carbon nanoparticles) or co-exposures to understand their relevance as markers of injury and intervention. Methodologies: C57BL/6 mice (5-7 weeks old) were used in this study following an approved protocol by the University of Cincinnati Institutional Animal Care and Use Committee (IACUC). The mice were exposed via oropharyngeal aspiration to multiwall carbon nanotube (MWCNT) particles suspension once (33 ugs/mouse) followed by housing for four weeks or to Cigarette smoke Extract (CSE) using a daily dose of 30µl/mouse for four weeks, or to co-exposure using the combined regime. Control groups received vehicles following the same dosing schedule. Lung toxicity/injury was assessed in terms of homeostasis changes in the lung tissue and lumen. Exposed lungs were analyzed for transcriptional expression of specific targets (AQPs, surfactant protein A, Mucin 5b) in relation to tissue homeostasis. Total RNA from lungs extracted using TRIreagent kit was analyzed using qRT-PCR based on gene-specific primers. Total protein in bronchoalveolar lavage (BAL) fluid was determined by the DC protein estimation kit (BioRad). GraphPad Prism 5.0 (La Jolla, CA, USA) was used for all analyses. Major findings: CNT exposure alone or as co-exposure with CSE increased the total protein content in the BAL fluid (lung lumen rinse), implying compromised membrane integrity and cellular infiltration in the lung alveoli. In contrast, CSE showed no significant effect. AQP1, required for water transport across membranes of endothelial cells in lungs, was significantly upregulated in CNT exposure but downregulated in CSE exposure and showed an intermediate level of expression for the co-exposure group. Both CNT and CSE exposures had significant downregulating effects on Muc5b, and SP-A expression and the co-exposure showed either no significant effect (Muc5b) or significant downregulating effect (SP-A), suggesting an increased propensity for infection in the exposed lungs. Conclusions: The current study based on the lung toxicity mouse model showed that both toxicant types, particles (CNT) versus chemicals (CSE), cause similar downregulation of lung innate defense targets (SP-A, Muc5b) and mostly a summative effect when presented as co-exposure. However, the two toxicant types show differential induction of aquaporin-1 coinciding with the corresponding differential damage to alveolar integrity (vascular permeability). Interestingly, this implies the potential of AQP1 as a differential marker of toxicant type-specific lung injury.

Keywords: aquaporin, gene expression, lung injury, toxicant exposure

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Authors: Dilek Ozturk, Narin Ozturk, Zeliha Pala Kara, Engin Kaptan, Serap Sancar Bas, Nurten Ozsoy, Alper Okyar

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Most physiological processes oscillate in a rhythmic manner in mammals including metabolism and energy homeostasis, locomotor activity, hormone secretion, immune and endocrine system functions. Endocrine body rhythms are tightly regulated by the circadian timing system. The hypothalamic-pituitary-thyroid (HPT) axis is under circadian control at multiple levels from hypothalamus to thyroid gland. Since circadian timing system controls a variety of biological functions in mammals, circadian rhythms of biological functions may modify the drug tolerability/toxicity depending on the dosing time. Selective mTOR (mammalian target of rapamycin) inhibitor everolimus is an immunosuppressant and anticancer agent that is active against many cancers. It was also found to be active in medullary thyroid cancer. The aim of this study was to investigate the dosing time-dependent toxicity of everolimus on the thyroid gland and hormones in mice. Healthy C57BL/6J mice were synchronized with 12h:12h Light-Dark cycle (LD12:12, with Zeitgeber Time 0 – ZT0 – corresponding to Light onset). Everolimus was administered to male (5 mg/kg/day) and female mice (15 mg/kg/day) orally at ZT1-rest period- and ZT13-activity period- for 4 weeks; body weight loss, clinical signs and possible changes in serum thyroid hormone levels (TSH and free T4) were examined. Histological alterations in the thyroid gland were evaluated according to the following criteria: follicular size, colloid density and viscidity, height of the follicular epithelium and the presence of necrotic cells. The statistical significance between differences was analyzed with ANOVA. Study findings included everolimus-related diarrhea, decreased activity, decreased body weight gains, alterations in serum TSH levels, and histopathological changes in thyroid gland. Decreases in mean body weight gains were more evident in mice treated at ZT1 as compared to ZT13 (p < 0.001, for both sexes). Control tissue sections of thyroid glands exhibited well-organized histoarchitecture when compared to everolimus-treated groups. Everolimus caused histopathological alterations in thyroid glands in male (5 mg/kg, slightly) and female mice (15 mg/kg; p < 0.01 for both ZT as compared to their controls) irrespective of dosing-time. TSH levels were slightly decreased upon everolimus treatment at ZT13 in both males and females. Conversely, increases in TSH levels were observed when everolimus treated at ZT1 in both males (5 mg/kg; p < 0.05) and females (15 mg/kg; slightly). No statistically significant alterations in serum free T4 levels were observed. TSH and free T4 is clinically important thyroid hormones since a number of disease states have been linked to alterations in these hormones. Serum free T4 levels within the normal ranges in the presence of abnormal serum TSH levels in everolimus treated mice may suggest subclinical thyroid disease which may have repercussions on the cardiovascular system, as well as on other organs and systems. Our study has revealed the histological damage on thyroid gland induced by subacute everolimus administration, this effect was irrespective of dosing time. However, based on the body weight changes and clinical signs upon everolimus treatment, tolerability for the drug was best following dosing at ZT13 in both male and females. Yet, effects of everolimus on thyroid functions may deserve further studies regarding their clinical importance and chronotoxicity.

Keywords: circadian rhythm, chronotoxicity, everolimus, thyroid gland, thyroid hormones

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Authors: B. S Kaith, K. Sharma, V. Kumar, S. Kalia

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Superabsorbent are three-dimensional networks of linear or branched polymeric chains which can uptake large volume of biological fluids. The ability is due to the presence of functional groups like –NH2, -COOH and –OH. Such cross-linked products based on natural materials, such as cellulose, starch, dextran, gum and chitosan, because of their easy availability, low production cost, non-toxicity and biodegradability have attracted the attention of Scientists and Technologists all over the world. Since natural polymers have better biocompatibility and are non-toxic than most synthetic one, therefore, such materials can be applied in the preparation of controlled drug delivery devices, biosensors, tissue engineering, contact lenses, soil conditioning, removal of heavy metal ions and dyes. Gums are natural potential antioxidants and are used as food additives. They have excellent properties like high solubility, pH stability, non-toxicity and gelling characteristics. Till date lot of methods have been applied for the synthesis and modifications of cross-linked materials with improved properties suitable for different applications. It is well known that ion beam irradiation can play a crucial role to synthesize, modify, crosslink or degrade polymeric materials. High energetic heavy ions irradiation on polymer film induces significant changes like chain scission, cross-linking, structural changes, amorphization and degradation in bulk. Various researchers reported the effects of low and heavy ion irradiation on the properties of polymeric materials and observed significant improvement in optical, electrical, chemical, thermal and dielectric properties. Moreover, modifications induced in the materials mainly depend on the structure, the ion beam parameters like energy, linear energy transfer, fluence, mass, charge and the nature of the target material. Ion-beam irradiation is a useful technique for improving the surface properties of biodegradable polymers without missing the bulk properties. Therefore, a considerable interest has been grown to study the effects of SHIs irradiation on the properties of synthesized semi-IPNs and IPNs. The present work deals with the preparation of semi-IPNs and IPNs and impact of SHI like O7+ and Ni9+ irradiation on optical, chemical, structural, morphological and thermal properties along with impact on different applications. The results have been discussed on the basis of Linear Energy Transfer (LET) of the ions.

Keywords: adsorbent, gel, IPNs, semi-IPNs

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Authors: Jaspreet Kaur, Parminder Nain, Vipin Saini, Sumitra Dahiya

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Elaeocarpus sphaericus has been traditionally used in the Indian traditional medicine system for the treatment of stress, anxiety, depression, palpitation, epilepsy, migraine and lack of concentration. The study was investigated to evaluate the neurological potential such as anxiolytic, muscle relaxant and sedative activity of methanolic extract of Elaeocarpus sphaericus stem bark (MEESSB) in mice. Preliminary phytochemical screening and acute oral toxicity of MEESSB was carried out by using standard methods. The anxiety was induced by employing Elevated Plus-Maze (EPM), Light and Dark Test (LDT), Open Field Test (OFT) and Social Interaction test (SIT). The motor coordination and sedative effect was also observed by using actophotometer, rota-rod apparatus and ketamine-induced sleeping time, respectively. Animals were treated with different doses of MEESSB (i.e.100, 200, 400 and 800 mg/kg orally) and diazepam (2 mg/kg i.p) for 21 days. Brain neurotransmitters like dopamine, serotonin and nor-epinephrine level were estimated by validated methods. Preliminary phytochemical analysis of the extract revealed the presence of tannins, phytosterols, steroids and alkaloids. In the acute toxicity studies, MEESSB was found to be non-toxic and with no mortality. In anxiolytic studies, the different doses of MEESSB showed a significant (p<0.05) effect on EPM and LDT. In OFT and SIT, a significant (p<0.05) increase in ambulation, rearing and social interaction time was observed. In the case of motor coordination activity, the MEESSB does not cause any significant effect on the latency to fall off from the rotarod bar as compared to the control group. Moreover, no significant effects on ketamine-induced sleep latency and total sleeping time induced by ketamine were observed. Results of neurotransmitter estimation revealed the increased concentration of dopamine, whereas the level of serotonin and nor-epinephrine was found to be decreased in the mice brain, with MEESSB at dose 800 mg/kg only. The study has validated the folkloric use of the plant as an anxiolytic in Indian traditional medicine while also suggesting potential usefulness in the treatment of stress and anxiety without causing sedation.

Keywords: anxiolytic, behavior experiments, brain neurotransmitters, elaeocarpus sphaericus

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Authors: Bouziane Zehaira

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Essential oils derived from aromatic or medicinal plants have recently proven useful in a variety of fields including the production of medicines, perfumes and foodstuffs. The purpose of this research is to determine the insecticidal activity of essential oils extracted from Mentha rotundifolia species against Aphis fabae. The bioassay used to determine essential oils toxicity to pest insect Aphis fabae revealed a very high effective repellent. The effect with concentrations of 100% and 30% were found to be statistically significant (F=64.800, P<0.0001) with an average of 7.66 and 7, respectively. According to the findings, the plant under consideration is promising as a source of natural pesticides and lends itself well to research in the field of pest control using biochemical alternatives.

Keywords: pest, mentha, activity, effective

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Authors: Eitedal Daoud, Reda M.Daoud, Khaled Abdel-Wahhab, Maha M.Saber, Lobna Saber

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Background: Cis-platin is a widely used chemotherapeutic drug to treat many malignant disorders including head and neck malignancies. Oto-nephrotxicity is an important and dose - limiting side effect of cis - platin therapy. Nowadays, more attention had been paid to oto-toxicity caused with cis-platin. Aim of the Work: This study was designed to investigate the potential protective effect of Whey protein (WP) against cis-platin induced ototoxicity compared to the effect of N-acetylcysteine (NAC) in rats. Methodology: Male albino rats were randomly divided into 6 groups: untreated rats (control), rats orally treated with whey protein (1g/kg b.w/day) for seven executive days, rats treated orally with N-acetylcysteine (500 mg/kgb.w /day) for seven executive days, rates intoxicated intraperitoneal (ip) with cis- platin (10 mg/kgb.w. once), rats treated with whey protein (1g/kgb.w./day) for seven executive days) followed by one injection (ip) of cis-platin(10 mg/kg b.w.) one hour after the last oral administration of whey protein, rats treated with N- acetylcysteine (for seven executive days followed by one injection (ip) of cis-platin (10 mg/kgb.w) one hour after the last oral administration of N-acetylcysteine. The organ of Corti, the stria vascularis and spiral ganglia were visualized by light microscopy at different magnifications. Results: Cis-platin intoxicated animals showed a significant decrease in serum level of total antioxidant capacity (TAC),with inhibition in the activity of serum glutathione-s transferase(GST) and paraoxonnase-1 (PON-1) in comparison with control. Group treated with either NAC or WP with cis-platin showed significant elevation in the activity of both GST & PON-1 with increased serum level of TAC when compared with cis-platin intoxicated rats. Animals treated with NAC or WP with cis-platin compared to those treated with cis-platin alone showed marked degree of improvement towards control rats as there was significant drop in the serum level of cortecosterone, nitric oxide (NO), and melandialdehyde (MDA).Histopathologic, in NAC pretreated group there was no changes in stria vascularis or spiral ganglia. In group pretreated with WP, there was no histopathologic alteration detected in the organ of Corti and Reissers membrane but oedema and haemorrhage were founded in the stria vascularis in small focal manner. Conclusion: Our finding showed that Whey protein is a natural dietary supplement product proved its ability of protection of anti-oxidant system and the cochlea against cis-platin induced ototoxicity.

Keywords: anti-oxidant, cis-platin, N-acetylcysteine, ototoxicity, whey protein

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Authors: K. Fraňa, M. Müller

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A presentation of the design of the Organic Rankine Cycle (ORC) with heat regeneration and super-heating processes is a subject of this paper. The maximum temperature level in the ORC is considered to be 110°C and the maximum pressure varies up to 2.5MPa. The selection process of the appropriate working fluids, thermal design and calculation of the cycle and its components are described. With respect to the safety, toxicity, flammability, price and thermal cycle efficiency, the working fluid selected is R134a. As a particular example, the thermal design of the condenser used for the ORC engine with a theoretical thermal power of 179 kW was introduced. The minimal heat transfer area for a completed condensation was determined to be approximately 520m2.

Keywords: organic rankine cycle, thermal efficiency, working fluids, environmental engineering

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Authors: Rim Frikha, Nouha Bouayed, Afifa Sellami, Nozha Chakroun, Salima Daoud, Leila Keskes, Tarek Rebai

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Introduction: Recurrent pregnancy loss (RPL) defined as two or more pregnancy losses, is a serious clinical problem. Methylene-tetrahydro-folate-reductase (MTHFR) polymorphisms, commonly the variant C677T is recognized as an inherited thrombophilia which might affect embryonic development and pregnancy success and cause pregnancy complications as RPL. Material and Methods DNA was extracted from peripheral blood samples and PCR-RFLP was performed for the molecular diagnosis of the C677T MTHFR polymorphism among 70 patients (35 couples) with more than 2 fetal losses. Aims and Objective: The aim of this study is to determine the frequency of MTHFR C677T among Tunisian couples with RPL and to critically analyze the available literature on the importance of MTHFR polymorphism testing in the management of RPL. Result and comments: No C677T mutation was detected in the carriers of RPL. This result would be related to sample size and to different criteria (number of abortion), - The association between MTHFR polymorphisms and pregnancy complications has been reported but with controversial results. - A lack of evidence for MTHFR polymorphism testing previously recommended by ACMG (American College of Medical medicine). Our study highlights the importance of screening of MTHFR polymorphism since the real impact of such thrombotic molecular defect on the pregnancy outcome is evident. - Folic supplementation of these patients during pregnancy can prevent such complications and lead to a successful pregnancy outcome.

Keywords: methylenetetrahydrofolate reductase, C677T, recurrent pregnancy loss, genetic testing

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Authors: Dmitriy Yu. Korulkin, Raissa A. Muzychkina

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The article represents the results of research of antitumor activity of different structural types of plant flavonoids extracted by authors from Polygonum L. plants in commercial reserves at the territory of the Republic of Kazakhstan. For the first time ever the results comparative research of antitumor activity of plant flavonoids of different structural groups and their synthetic derivatives have been represented. The results of determination of toxicity of flavonoids in single parenteral infusion conditions have been represented. Experimental substantiation of possible mechanisms of antiproliferative and cytotoxic action of flavonoids has been suggested. The perspectives of usage of plant flavonoids as medications and creation of effective dosage forms of antitumor medicines on their basis have been substantiated.

Keywords: antitumor activity, cytotoxicity, flavonoids, Polygonum L., secondary metabolites

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Authors: Hyunsang Kim, Younghun Kim, Younghee Kim, Sangku Lee

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We investigated ecotoxicity and performed an experiment for removing ZnO nanoparticles in water. Short-term exposure of hatching test using fertilized eggs (O. latipes) showed deformity in 5 ppm of ZnO nanoparticles solution, and in 10ppm ZnO nanoparticles solution delayed hatching was observed. Herein, chemical precipitation method was suggested for removing ZnO nanoparticles in water. The precipitated ZnO nanoparticles showed the form of ZnS after addition of Na2S, and the form of Zn3(PO4)2 for Na2HPO4. The removal efficiency of ZnO nanoparticles in water was closed to 100% for two case. In ecotoxicity evaluation of as-precipitated ZnS and Zn3(PO4)2, they did not cause any acute toxicity for D. magna. It is noted that this precipitation treatment of ZnO is effective to reduce the potential cytotoxicity.

Keywords: ZnO nanopraticles, ZnS, Zn3(PO4)2, ecotoxicity evaluation, chemical precipitation

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Authors: M. Elder, L. Beech, A. Mackie

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Heterotopic pregnancy is an uncommon and potentially life-threatening condition in which there is simultaneous occurrence of intrauterine and ectopic pregnancies. It has an incidence of approximately 1:3900 pregnancies, occurring in only 1:30000 spontaneous pregnancies. This study presents a rare case of spontaneous heterotopic pregnancy in a 34-year-old primiparous woman who was brought in by ambulance to the emergency department following collapse at 20+1 weeks gestation after normal first trimester screening and morphology scan. She was hemodynamically unstable and fetal heart rate was 60bpm. Initial resuscitation included transfusion of 2 units packed red blood cells and 1g intravenous tranexamic acid. Bedside ultrasound revealed evidence of approximately 1000ml clot in the right upper quadrant. She underwent a diagnostic laparoscopy and washout, which proceeded to a midline exploratory laparotomy. This revealed a 2.6L hemoperitoneum and query right ectopic pregnancy with calcified areas and clot, with no other cause of bleeding identified. Right salpingectomy was performed, and pathology later confirmed ectopic pregnancy. The intrauterine pregnancy had no complications, and she delivered a healthy full-term baby. This case demonstrates that ultrasound confirmation of intrauterine pregnancy does not exclude coexisting ectopic pregnancy. Heterotopic pregnancy should be considered in any pregnant woman presenting with abdominal pain or signs of hemorrhagic shock, as prompt diagnosis and treatment is essential to minimize foetal and maternal morbidity and mortality.

Keywords: ectopic pregnancy, hemorrhagic shock, salpingectomy, spontaneous heterotopic pregnancy

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Authors: Sara Ataei, Mohammad Bagher Oghazian, Mania Radfar

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We describe a patient with hypercalcemia associated with the injection of high doses vitamin D as supplement for a period of six months. A 76-year-old woman had been taking an intramuscular injection of vitamin D 300,000 IU every ten days for six months. She was hospitalized with symptoms of hypercalcemia: chronic constipation, unstable gait, a chronic generalized musculoskeletal pain and increased fatigue. On admission her 25 (OH) vitamin D and Calcium levels were 559 nmol/L and 13.85 mg/dL respectively, and Parathyroid Hormone (PTH) level was 7.1 pg/mL. Immediately she received diuresis therapy with saline and furosemide in conjunction with calcitonin and pamidronate. At discharge her serum calcium level was 11.5 mg/dL. To lower endogenous overproduction of calcitriol, prednisolone 20 mg/day for 10 days was administered at discharge time.

Keywords: vitamin D, hypercalcemia, vitamin D toxicity, parathyroid hormone

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Authors: Somayeh Fani, Mahmood Ameen Abdulla

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Costus speciosus is an important Malaysian medicinal plant commonly used traditionally in the treatment of many aliments. The present investigation is designed to elucidate preventive effects of ethanolic extracts of C. speciosus rhizome against absolute ethanol-induced gastric mucosal injury in Sprague-Dawley rats. Five groups of rats were orally pre-treated with vehicle, carboxymethylcellulose (CMC) as normal control group (Group 1), ethanol as ulcer control group (Group 2), omeprazole 20 mg/kg (reference group) (Group 3), and 250 and 500 mg/kg of C. speciosus extract (experimental groups) (Group 4 and 5), respectively. An hour later, CMC was given orally to Group 1 rats and absolute ethanol was given orally to Group 2-5 rats to generate gastric mucosal injury. After an additional hour, the rats were sacrificed. Grossly, ulcer control group exhibited severe of gastric mucosal hemorrhagic injury and increased in ulcer area, whereas groups pre-treated with omeprazole or plant’s rhizomes exhibited the significant reduction of gastric mucosal injury. Significant increase in the pH and mucous of gastric content was observed in rats re-treated with C. speciosus rhizome. Histology, ulcer control rats, demonstrated remarkable disruption of gastric mucosa, increased in edema and inflammatory cells infiltration of submucosal layer compared to rats pre-treated with rhizomes extract. Periodic acid Schiff staining for glycoprotein, rats pre-fed with C. speciosus C. displayed remarkably intense uptake of magenta color by glandular gastric mucosa compared with ulcer control rats. Immunostaining of gastric epithelium, rats pre-treatment with rhizome extract provide evidence of up-regulation of HSP70 and down-regulation of Bax proteins compared to ulcer control animals. Gastric tissue homogenate, C. speciosus significantly increased the activity of superoxide dismutase (SOD), and catalase (CAT), increased the level of non-protein sulfhydryl (NP-SH) and decreased the level of lipid peroxidation after ethanol administration. Acute toxicity test did not show any signs of toxicity. The mechanisms implicated the gasrtoprotective property of C. speciosus depend upon the antisecretory activity, increased in gastric mucus glycoprotein, up-regulation of HSP70 protein and down-regulation of Bax proteins, reduction in the lipid peroxidation and increase in the level of NP-SH and antioxidant enzymes activity in gastic homogenate.

Keywords: antioxidant, Costus speciosus, gastric ulcer, histology, omeprazole

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Authors: Maki Mizogami, Hironori Tsuchiya, Yoshiroh Hayabuchi, Kenji Shigemi

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Since drugs exhibit significant structure-dependent differences in activity and toxicity, their differentiation based on the mechanism of action should have implications for comparative drug efficacy and safety. We aimed to differentiate drug stereoisomers by their stereostructure-selective membrane interactions underlying pharmacological and toxicological effects. Biomimetic lipid bilayer membranes were prepared with phospholipids and sterols (either cholesterol or epicholesterol) to mimic the lipid compositions of neuronal and cardiomyocyte membranes and to provide these membranes with the chirality. The membrane preparations were treated with different classes of stereoisomers at clinically- and pharmacologically-relevant concentrations (25-200 μM), followed by measuring fluorescence polarization to determine the membrane interactivity of drugs to change the physicochemical property of membranes. All the tested drugs acted on lipid bilayers to increase or decrease the membrane fluidity. Drug stereoisomers could not be differentiated when interacting with the membranes consisting of phospholipids alone. However, they stereostructure-selectively interacted with neuro-mimetic and cardio-mimetic membranes containing 40 mol% cholesterol ((3β)-cholest-5-en-3-ol) to show the relative potencies being local anesthetic R(+)-bupivacaine > rac-bupivacaine > S(‒)-bupivacaine, α2-adrenergic agonistic D-medetomidine > rac-medetomidine > L-medetomidine, β-adrenergic antagonistic R(+)-propranolol > rac-propranolol > S(–)-propranolol, NMDA receptor antagonistic S(+)-ketamine > rac-ketamine, analgesic monoterpenoid (+)-menthol > (‒)-menthol, non-steroidal anti-inflammatory S(+)-ibuprofen > rac-ibuprofen > R(‒)-ibuprofen, and bioactive flavonoid (+)-epicatechin > (‒)-epicatechin. All of the order of membrane interactivity were correlated to those of beneficial and adverse effects of the tested stereoisomers. In contrast, the membranes prepared with epicholesterol ((3α)-chotest-5-en-3-ol), an epimeric form of cholesterol, reversed the rank order of membrane interactivity to be S(‒)-enantiomeric > racemic > R(+)-enantiomeric bupivacaine, L-enantiomeric > racemic > D-enantiomeric medetomidine, S(–)-enantiomeric > racemic > R(+)-enantiomeric propranolol, racemic > S(+)-enantiomeric ketamine, (‒)-enantiomeric > (+)-enantiomeric menthol, R(‒)-enantiomeric > racemic > S(+)-enantiomeric ibuprofen, and (‒)-enantiomeric > (+)-enantiomeric epicatechin. The opposite configuration allows drug molecules to interact with chiral sterol membranes enantiomer-selectively. From the comparative results, it is speculated that a 3β-hydroxyl group in cholesterol is responsible for the enantioselective interactions of drugs. In conclusion, the differentiation of drug stereoisomers by their stereostructure-selective membrane interactions would be useful for designing and predicting drugs with higher activity and/or lower toxicity.

Keywords: chiral membrane, differentiation, drug stereoisomer, enantioselective membrane interaction

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