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1.  Synthesis and Biological Evaluation of Thiosemicarbazide Derivatives Endowed with High Activity toward Mycobacterium Bovis 
Thiosemicarbazides are potent intermediates for the synthesis of pharmaceutical and bioactive materials and thus, they are used extensively in the field of medicinal chemistry. The imine bond (-N=CH-) in this compounds are useful in organic synthesis, in particular for the preparation of heterocycles and non-natural β-aminoacids. In this paper the synthesis of some new thiosemicarbazide derivatives by condensation reaction of various aldehydes or ketones with 4-phenylthiosemicarbazide or thiosemicarbazide is reported. This synthesis method has the advantages of high yields and good bioactivity. The structures of these compounds were confirmed by IR, mass, 1H NMR, 13C NMR, and single-crystal X-ray diffraction studies. All of these compounds were tested for their in-vitro anti-mycobacterial activity. The influence of the functional group and position of substituent on anti-bacterial activity of compounds is investigated too. The preliminary results indicated that all of the tested compounds showed good activity against the test organism. The compounds 11 and 30 showed the highest anti-tubercular activity (0.39 μg/mL). This synthesis method has the advantages of high yields and good bioactivity.
PMCID: PMC5610766
Thiosemicarbazide derivatives; Biological evaluation; Mycobacterium bovis; Anti-tubercular activity; Medicinal chemistry
2.  Formulation Development and Evaluation of the Therapeutic Efficacy of Brinzolamide Containing Nanoemulsions 
Brinzolamide (BZ) is an intraocular pressure reducing agent with low bioavailability. The purpose of the present study was to overcome this issue by development of BZ containing nanoemulsions (NEs) as an ocular drug delivery system with desirable therapeutic efficacy. Brinzolamide NEs were prepared by the spontaneous emulsification method. Based on initial release studies, twelve formulations with the slowest release characteristics were subjected to further physicochemical investigations such as particle size, polydispersity index, pH, refractive index, osmolality and viscosity. The therapeutic efficacy of these formulations was assessed by measuring the intraocular pressure after instillation of the prepared NEs in normotensive albino rabbit eyes. Nanoemulsions with suitable physicochemical properties exhibited high formulation stability under different conditions. more over biological evaluations indicated that using lower drug concentrations in NE formulations (0.4%) had a similar or even better pharmacodynamic effect compared to the commercial suspension with a higher drug concentration (1%). Our findings suggest that NEs could be effectively used as carriers for enhancing the bioavailability of topically applied ophthalmic drugs.
PMCID: PMC5610741
Ocular drug delivery; Brinzolamide; Nanoemulsion; Physicochemical characterization; Ocular bioavailability; Therapeutic efficacy
3.  A New Approach to Antivenom Preparation Using Chitosan Nanoparticles Containing EchisCarinatus Venom as A Novel Antigen Delivery System 
In recent years, use of biodegradable polymers based nanoparticles has received high interest in the development of vaccines delivery vehicles. The aim of study was to prepare chitosan nanoparticles (CS NPs) for loading Echis carinatus (EC) venom and evaluate their potential as an adjuvant and antigen delivery system on a pilot scale. CS NPs were prepared using ionic gelation method, and their characteristics were optimized. Venom-loaded CS NPs prepared under optimum conditions and traditional venom-loaded adjuvants were used to hyperimmunization of horse. Under optimum conditions, particle size, polydispersity index (PDI), and zeta potential of CS NPs were 127.9 ± 15 nm, 0.29, and +19.8 ± 1.92 mV, while those of venom-loaded CS NPs were 182.4 ± 20 nm, 0.35, +26.8 ± 1.98 mv, respectively. All CS NPs had integrated surface and good morphology. Optimum loading concentration of EC venom was 500 µg/mL. The loading capacity (LC) and loading efficiency (LE) were 87% and 94%, respectively, and release profile of venom-loaded CS NPs showed suitable correlation with Higuchi kinetics. Stability test showed good stability of the venom encapsulated in CS NPs. Furthermore, antivenom plasma obtained using the new antigen delivery system had significantly higher potency (P < 0.05) for neutralizing the venom than that obtained using conventional system. These results suggested that venom-loaded CS NPs could be a suitable alternative to conventional adjuvant for development antivenom.
PMCID: PMC5610742
Chitosan; Nanoparticles; Echiscarinatus venom; Adjuvant; Hyperimmune plasma
4.  Anticancer Activity of Curcumin-Loaded PLGA Nanoparticles on PC3 Prostate Cancer Cells 
Curcumin (Cur) has been found to be very efficacious against many different types of cancer cells. However, the major disadvantage associated with the use of Cur is its low systemic bioavailability. Our present work investigated the toxic effect of encapsulation of Cur in PLGA (poly lactic-coglycolic acid) nanospheres (NCur) on PC3 human cancer prostate cell. In the present study, we have investigated the effects of NCur on growth, autophagia, and apoptosis in PC3 cells, respectively, by MTT assay, fluorescence microscopy, and Flow cytometry. MTT assays revealed that the NCur at the concentration of 25 µg/mL for 48 h were able to exert a more pronounced effect on the PC3 cells as compared to free Cur. Apoptotic index was significantly increased in NCur-treated cells compared to free Cur. The percentage of autophagic cells (LC3-II positive cells) was also significantly increased in NCur treatment in comparison to free Cur. These data indicate that the NCur has considerable cytotoxic activity more than Cur on PC3 cell lines, which is mediated by induction of both apoptotic and autophagic processes. Thus, NCur has high potential as an adjuvant therapy for clinical application in prostate cancer.
PMCID: PMC5610743
Programmed cell death; Prostate cancer; Curcumin; Nanoparticles; PLGA
5.  Docking Studies, Synthesis, and In-vitro Evaluation of Novel Oximes Based on Nitrones as Reactivators of Inhibited Acetylcholinesterase 
Acetylcholinesterase has important role in synaptic cleft. It breaks down the acetylcholineat cholinergic synapsesand terminates the cholinergic effects. Some chemical agents like organophosphorus compounds (OPCs) including nerve agents and pesticides react with acetylcholinesteraseirreversibly. They inhibit normal biological enzyme action and result in accumulation of acetylcholineand show toxic effects andcholinergic symptoms. The process of Acetylcholinesterase (AChE) inhibition can be reversed by a nucleophilic agent to dephosphorylate and reactivate the enzyme. In this study, design and docking studies of 15 novel nitrone based onoximes as reactivators were performed by using AutoDock program. Then, more effective reactivatorsoximes in terms of binding energy and orientation within the active site were synthesized and evaluated in-vitro on human AChE (hAChE) inhibited by paraoxon and compared to standard hAChE reactivators (2-PAM and obidoxime). Our results used to design new derivatives of Oxim with better efficacy than 2-PAM and obidoxime. Syntheses of some selected bis-pyridiniumoximes based on the nitrones are underway.
PMCID: PMC5610744
Reactivators; Oximes; Molecular docking; Nitrones; Organophosphorus compounds
6.  Anticonvulsant Effects of New 1, 4-DihydropyridineDerivatives Containing Imidazolyl Moiety Against Seizures Induced by Pentylenetetrazole and Maximal Electroshock in Mice 
Epilepsy is a chronic disorder of the brain affecting around 50 million people in the world. Up to 30% of epileptic patients do not respond to available drugs and medical therapies. In this paper, anticonvulsant screening of 10 synthesized new derivatives of 1, 4-dihydropyridine-3, 5-dicarboxamides was performed.
Anticonvulsant activity was evaluated by intravenous and intraperitoneal pentylenetetrazole and maximal electroshock induced seizures tests. Nifedipine was used as reference drug. Our pharmacological results revealing the compounds 2, 4, 5, and 6 can be effective in both absence and grandmal seizures in human.
These pharmacological studies have displayed that these new dihydropyridine derivatives are capable to inhibiting seizures induced by pentylenetetrazole and maximal electroshock in mice efficiently.
PMCID: PMC5610745
Dihydropyridine; Imidazole; Anticonvulsant; Pentylenetetrazole; Maximal Electroshock
7.  Synthesis and Leishmanicidal Activity of 1-[5-(5-Nitrofuran-2-yl)-1, 3, 4-Thiadiazole-2-yl]-4-BenzoylePiperazines 
A series of (5-nitrofuran-2-yl)-1, 3, 4-thiadiazole-2-yl derivatives 6a–6e have been synthesized and screened for in-vitro anti-leishmanial activity against the promastigote form of L. major. The structure of Schiff bases were confirmed by 1H NMR, IR. Screening results indicate that all of the designed and synthesized final compounds (6a-6e) significantly reduced the viability of promastigotes of L. major in comparison toglucantime (IC50 3× 103 μg/mL). Meta and Para substitutions in benzene ring containing compounds were more potent than other derivative and the most potent compounds were 6d, 6e with IC50 value 94 µm and 77.6 µm, respectively. The experimental data proposes that (5-nitrofuran-2-yl)-1, 3, 4-thiadiazole-2-yl derivatives may be further investigated as a candidate drug for treatment of cutaneous leishmaniasis.
PMCID: PMC5610746
1; 3; 4-Thiadiazole; Nitrofuran; Antileishmanial activity; Leishmania Major; Promastigote
8.  Pharmacophore Based Virtual Screening Approach to Identify Selective PDE4B Inhibitors 
Phosphodiesterase 4 (PDE4) has been established as a promising target in asthma and chronic obstructive pulmonary disease. PDE4B subtype selective inhibitors are known to reduce the dose limiting adverse effect associated with non-selective PDE4B inhibitors. This makes the development of PDE4B subtype selective inhibitors a desirable research goal. To achieve this goal, ligand based pharmacophore modeling approach is employed. Separate pharmacophore hypotheses for PDE4B and PDE4D inhibitors were generated using HypoGen algorithm and 106 PDE4 inhibitors from literature having thiopyrano [3,2-d] Pyrimidines, 2-arylpyrimidines, and triazines skeleton. Suitable training and test sets were created using the molecules as per the guidelines available for HypoGen program. Training set was used for hypothesis development while test set was used for validation purpose. Fisher validation was also used to test the significance of the developed hypothesis. The validated pharmacophore hypotheses for PDE4B and PDE4D inhibitors were used in sequential virtual screening of zinc database of drug like molecules to identify selective PDE4B inhibitors. The hits were screened for their estimated activity and fit value. The top hit was subjected to docking into the active sites of PDE4B and PDE4D to confirm its selectivity for PDE4B. The hits are proposed to be evaluated further using in-vitro assays.
PMCID: PMC5610747
Phosphodiesterase 4; Pharmacophore; HypoGen; Virtual screening; Zinc database; docking
9.  Evaluation of Novel α-(Acyloxy)-α-(Quinolin-4-yl) Acetamides as Antiplasmodial Agents 
Because of expanding resistance to efficient and affordable antimalarial drugs like chloroquine, the search is continuing for more effective drugs against this disease. In-vitro antiplasmodial activity and cytotoxicity of α-(acyloxy)-α-(quinolin-4-yl) acetamides on Plasmodium falciparum and structure-activity relationships of this new class of Passerini adducts is described. The in-vitro antiplasmodial activity of compounds was tested against chloroquine sensitive 3D7 strain. Toxicity of active compounds was investigated on HepG2 cell line. Compounds 1, 20 and 22 showed significant antiplasmodial activity with IC50 value of 1.511, 1.373 and 1.325 µM, respectively. The active compounds did not show noticeable toxicity when tested against HepG2 cell line. The present results bring essential elements which will be used for the synthesis of more active derivatives of α-(acyloxy)-α-(quinolin-4-yl) acetamides.
PMCID: PMC5610748
Plasmodium falciparum; Quinolines; Cytotoxicity; HepG2; 3D7 strain
10.  Design and Synthesis of Some Novel Fluorobenzimidazoles Substituted with Structural Motifs Present in Physiologically Active Natural Products for Antitubercular Activity 
Keeping in view the drawbacks associated with research on anti-TB drugs based on plant extracts and the non-availability of fluorinated natural products with antitubercular activity has prompted us to make an effort towards the synthesis and characterization of a novel series of fifteen substituted fluorobenzimidazoles. The newly synthesized compounds were characterized by I.R, 1H-NMR, 13C-NMR, Mass, and elemental analysis. The synthesized compounds 4(a-f) and 5(b-j) have been evaluated for their in-vitro antimycobacterial activity against H37Rv strain (ATCC 27294) by MABA method. Incorporation of methylenedioxyphenyl moiety at 2- and 6-position of the benzimidazole ring furnished compounds 4d and 5i with antitubercular activity comparable or more potent than the naturally occurring compounds with reported antitubercular activity. Among the fifteen tested compounds, 4d and 5i emerged as promising hits characterized by MIC lower than that determined for sesamin against the pathogenic H37Rv strain. Antitubercular activity results indicate that these compounds may be suitable for further lead optimization. The cytotoxic effect of these active compounds on THP-1 cell line was assessed by MTT assay and the results suggest that these two molecules are potential candidates for further development as antitubercular agents.
PMCID: PMC5610749
Fluorobenzimidazole; Antitubercular activity; Mycobacterium tuberculosis; H37Rv strain; Natural products
11.  Synthesis and Evaluation of the Antimicrobial Activity of Spiro-4H-pyran Derivatives on Some Gram Positive and Gram Negative Bacteria 
Infections are one of the most important causes of death, disability and inappropriate conditions for millions of people around the world. Therefore, the development in prognosis, prevention and treatment of infectious diseases made a considerable progress in designing and synthesis of new antimicrobial drugs. Nowadays, due to the increase in microbial resistance, discovery of new compounds with broad spectrum effects is granted. 4H-pyran derivatives and spiro compounds are the most important fragments in some effective drugs with antimicrobial activity. Therefore, in this study, 6 compounds with spiro-4H-pyran core were synthesized and evaluated for their antimicrobial activity against four different bacterial species using microbroth dilution and disk diffusion methods. Minimum inhibitory concentration (MIC) has been measured for each compound and also for the standard antibiotic, gentamicin, and they were all compared together. According to our result, one of the spiropyran derivative (5d) containing both the indole and the cytosine ring, has been shown good antibacterial effects against standard and clinical isolates of Staphylococcus aureus and Streptococcus pyogenes.
PMCID: PMC5610750
Spiro-4H-pyran; one-pot reaction; three-component reaction; Staphylococcus aureus; Streptococcus pyogenes; Microbroth dilution; Disk diffusion
12.  Esters of Quinoxaline 1ˏ4-Di-N-oxide with Cytotoxic Activity on Tumor Cell Lines Based on NCI-60 Panel 
Quinoxalines display diverse and interesting pharmacological activities as antibacterial, antiviral, antiparasitic and anticancer agents. Particularly, their 1ˏ4-di-N-oxide derivatives have proved to be cytotoxic agents that are active under hypoxic conditions as that of solid tumours. A new series of quinoxaline 1ˏ4-di-N-oxide substitutes at 7-position with esters group were synthetized and characterized by infrared (IR), proton nuclear magnetic resonance (1H-NMR), spectroscopy, and elemental analysis. Seventeen derivatives (M1-M3, E1-E8, P1-P3 and DR1-DR3) were selected and evaluated for antitumor activities using the NCI-60 human tumor cell lines screen. Results showed that E7, P3 and E6 were the most active compounds against the cell lines tested. Substitutions at 7-position with esters group not necessarily affect the biological activity, but the nature of the esters group could exert an influence on the selectivity. Additionally, substitutions at 2-position influenced the cytotoxic activity of the compounds.
PMCID: PMC5610751
Antitumor; Cancer; Drugs; Esters; Quinoxaline 1; 4-di-N-oxide
13.  QSAR Study of 17β-HSD3 Inhibitors by Genetic Algorithm-Support Vector Machine as a Target Receptor for the Treatment of Prostate Cancer 
The 17β-HSD3 enzyme plays a key role in treatment of prostate cancer and small inhibitors can be used to efficiently target it. In the present study, the multiple linear regression (MLR), and support vector machine (SVM) methods were used to interpret the chemical structural functionality against the inhibition activity of some 17β-HSD3inhibitors. Chemical structural information were described through various types of molecular descriptors and genetic algorithm (GA) was applied to decrease the complexity of inhibition pathway to a few relevant molecular descriptors. Non-linear method (GA-SVM) showed to be better than the linear (GA-MLR) method in terms of the internal and the external prediction accuracy. The SVM model, with high statistical significance (R2train = 0.938; R2test = 0.870), was found to be useful for estimating the inhibition activity of 17β-HSD3 inhibitors. The models were validated rigorously through leave-one-out cross-validation and several compounds as external test set. Furthermore, the external predictive power of the proposed model was examined by considering modified R2 and concordance correlation coefficient values, Golbraikh and Tropsha acceptable model criteriaʹs, and an extra evaluation set from an external data set. Applicability domain of the linear model was carefully defined using Williams plot. Moreover, Euclidean based applicability domain was applied to define the chemical structural diversity of the evaluation set and training set.
PMCID: PMC5610752
QSAR; Genetic algorithms; Support vector machine; Multiple linear regressions; 17β-HSD3
14.  Evaluation of a 99mTc-tricine Vascular Disrupting Agent as an In-vivo Imaging in 4T1 Mouse Breast Tumor Model  
Colchicine as a vascular disrupting agent creates microtubule destabilization which induces vessel blockage and consequently cell death. Accordingly, colchicines and its analogues radiolabeled with 99mTc may have potential for visualization of tumor. In this work, deacetylcolchicine a colchicine analogue was labeled with 99mTc via tricine as a coligand and characterized for its tumor targeting properties. The in-vitro radiochemical stability and the biodistribution were studied in 4T1 breast tumor model bearing mice. Labeling yield of more than 90% was obtained corresponding to a specific activity of 46 MBq/µmol. In-vivo biodistribution studies demonstrated that radiocomplex had high tumor to muscle and tumor to blood ratios at early time points. Planer gamma imaging of tumor bearing mice showed that this radioconjugate was able to clearly visualize tumors. According to high tumor uptake, presented radiocomplex may have a potential for targeted imaging studies.
PMCID: PMC5610754
Deacetylcolchicine; Labeling; Pharmacokinetics; Tricine; 4T1 Tumor
15.  Thermo-, Radio- and Photostability of Perindopril Tert-butyloamine in The Solid State. Comparison to Other Angiotensin Converting Enzyme Inhibitors 
The main aim of this study was determination of thermo- radio- and photostability of perindopril tert-butyloamine (PER) therefore the efficiency and safety of the therapy could be maintained.
A chromatographic method (RP-HPLC) had been validated before use to determine PER loss. The evaluation of stability properties of PER in solid state under the influence of isothermal condition, relative humidity - RH = 0% and 76.4%, exposure to 6 mln lux h and ionizing radiation generated by beam of electrons of 25–400 kGy was investigated.
Studies pointed out that presence of moisture changes a kinetic model of PER degradation; lack of moisture in the air generates a first-order kinetic model of the reaction, increase humidity generates the autocatalytic model. PER proved to be resistant for ionizing radiation. It is possible to use radiation sterilization and decontamination (dose 25 kGy) with no significant loss of content. Investigation of PER photostability proved, that after exposure to 6 mln lux h physicochemical parameters are acceptable. Among all the ACE-I, PER has one of the shortest t0,5. PER should be stored in closed containers, protected from high temperature and moisture. PER is referred to be photostable and resistant for radiodegradation.
PMCID: PMC5610755
Perindopril tert-butyloamine; Stability; Photostability; Radiodegradation; ACE-I
16.  Voltammetric Determination of Penicillamine Using a Carbon Paste Electrode Modified with Multiwall Carbon Nanotubes In the Presence of Methyldopa as a Mediator 
A multiwall carbon nanotubes-modified carbon paste electrode (MWCNTs/MCPE) was fabricated and used to study the electrooxidation of penicillamine (PA) by electrochemical methods in the presence of methyldopa (MDOP) as a homogeneous mediator. The electrochemical oxidation of PA on the new sensor has been carefully studied. The kinetic parameters such as electron transfer coefficient, α, and catalytic reaction rate constant, K/h, were also determined using electrochemical approaches. The electrocatalytic oxidation peak current of PA showed a linear dependent on the PA concentrations and linear calibration curves were obtained in the ranges of 0.2-250.0 µM of PA concentration with square wave voltammetry (SWV) method. The detection limit (3σ) was determined as 0.1 µM. This sensor was also examined as a fast, selective, simple and precise new sensor for voltammetric determination of PA in real samples such as drug and urine.
PMCID: PMC5610756
Penicillamine; Multiwall carbon nanotubes; Modified electrode; Sensor; Electrocatalysis
17.  Determination of Aluminum in Dialysis Concentrates by Atomic Absorption Spectrometry after Coprecipitation with Lanthanum Phosphate 
This method was developed for the determination of trace amounts of aluminum(III) in dialysis concentrates using atomic absorption spectrometry after coprecipitation with lanthanum phosphate. The analytical parameters that influenced the quantitative coprecipitation of analyte including amount of lanthanum, amount of phosfate, pH and duration time were optimized. The % recoveries of the analyte ion were in the range of 95-105 % with limit of detection (3s) of 0.5 µg l-1. Preconcentration factor was found as 1000 and Relative Standard Deviation (RSD) % value obtained from model solutions was 2.5% for 0.02 mg L-1. The accuracy of the method was evaluated with standard reference material (CWW-TMD Waste Water). The method was also applied to most concentrated acidic and basic dialysis concentrates with satisfactory results.
PMCID: PMC5610757
Aluminum; Lanthanium phosphate; Coprecipitation; Dialysis concentrate; Atomic absorption spectrometer
18.  Development of a New Method Based on Chiral Ligand-Exchange Chromatography for the Enantioseparation of Propranolol 
A new chromatographic procedure was proposed for the separation of propranolol (PRN) enantiomers based upon enantioselective chiral ligand-exchange chromatography. The separation was carried out on a short C8 column leading to considerably short separation time. L-alanine and Cu2+ were applied as chiral selector and central bivalent complexing ion, respectively. It was found that the kind of copper salt could influence the enantioseparation efficiency. The separation on the C8 stationary phase was more efficient than that on the C18 column. It was shown that the pH of mobile phase, organic modifier content of mobile phase, mole ratio of chiral ligand to bivalent ion and Cu (L-alanine) 2 concentration in the mobile phase were important in enantioseparation efficiency. Water/methanol (70:30) mixture containing L-alanine-Cu2+ (7:1) was found to be the best mobile phase condition for PRN enantioseparation. All effective parameters were optimized in order to improve the separation efficiency. The optimized HPLC method was utilized for analysis of propranolol enantiomers in spiked human blood plasma samples.
PMCID: PMC5610758
L-alanine; chiral separation; Propranolol; C8 column; Ligand exchange
19.  Simultaneous Determination of Residue from 58 Pesticides in the Wheat Flour Consumed in Tehran, Iran by GC/MS 
Food safety has a direct impact on human health and as such is a growing concern worldwide. Presence of harmful pesticide residue in food is a serious cause for concern among consumers so it is important to monitor levels of pesticides in foods. The aim of this study was simultaneous determination of concentrations of 58 pesticides in 40 wheat flour samples collected from Tehran market in January, 2014. The city under study (Tehran) was divided into five districts and samples were collected independently from each district and sourced from different bakeries (n=40). A gas chromatography-mass spectrometry single quadrupole selected ion monitoring «GC/MS-SQ-SIM» method was used to quantify residue of 58 pesticides in the wheat flour samples. Four of the 40 samples showed contamination with Malathion (2 samples: 50.96 ± 11.38 and 62.088 ± 11.38 ppb) and 2, 4-DDE (2 samples: 19.88±15.24 and 13.7 ± 15.24 ppb). that had levels below MRLs of these pesticides in Iran. Averages of recovery of pesticides at 6 concentration levels were in the range of 81.61-118.41%. The method was proven as repeatable with RSDr in the range of 6.5-29.45% for all concentration levels. The limit of quantification for 37 of the tested pesticides was calculated as 15 ppb and for the other 21 tested pesticides, the concentration was 25 ppb. In summary, results of these tests suggested that the wheat flour consumed in Tehran, was within safety limits in terms of levels of pesticide residues.
PMCID: PMC5610759
Pesticides; GC/MS; Wheat flour; Food safety.
20.  Comparison of Kinetic Study and Protective Effects of Biological Dipeptide and Two Porphyrin Derivatives on Metal Cytotoxicity Toward Human Lymphocytes 
In this research, dipeptide (his-β-alanine) and porphyrin derivatives were choosen for comparing chelating ability of toxic metals such as Al3+, Cu2+, Hg2+ and Pb2+ in-vitro. The reason for choosing these two compounds is that both of them are naturally present in biological systems and comparison of chelating ability of these two compounds has not yet been done. Synthesis and comparison of kinetic study of dipeptide (his-β-alanine), meso-tetrakis(4-trimethylanilinium) porphyrin (TAPP) and Tetrakis(4-sulfonatophenyl)porphyrin (TPPS4) were carried out by our team. In addition, cytotoxicity assays of metals and chelators were also performed using methylthiazoletetrazolium (MTT) test. Furthermore we investigated the protective effect of chelators against cytotoxicity, induced by differenrt toxic metals such as Al3+, Cu2+, Hg2+ and Pb2+ on human lymphocytes. EC50 values on human lymphocytes obtained after 12 h. incubation for Al3+, Cu2+ and Hg2+ were 30, 51, 3 µM respectively and for Pb2+ no cytotoxicity was observed on human lymphocyte up to 1000 µM concentration. EC50 obtained for chelators dipeptide, TPPS4 and TAPP were 948, 472 and 175 µM respectively. Pretreatment of human lymphocyte with subtoxic concentations of chelators reduced toxicity of the metals against human blood lymphocytes.
PMCID: PMC5610760
Dipeptide; Porphyrin; Chelator; Toxic metals; Cytotoxicity; EC50; lymphocytes
21.  Toxicity Assessment of Asteraceae Centaurea Repens L Extract in Mice 
The species Asteraceae Centaurea repens (Asteraceae), known as Acroptilon repens, and Talkhe in persian is used in folk medicine as an emetic, anti-epileptic, and anti-malaria herb in many parts of the world but its toxic effects have not determined yet. This study aimed to evaluate the acute and subchronic toxicity of this extract to find its possible adverse health effects through clinical, hematological, biochemical, and histopathological endpoints in both gender of mice. Aerial parts of the plant were air-dried and the terpene extract of aerial parts of plant was provided by percolation using methanol, petroleum ether, and diethyl ether. All clinical, biochemical and histopathological changes were assessed in appropriate endpoints and compared with control group. Although no mortality was seen in acute study by administrating doses up to 2000 mg/kg, repeated dose study on 1000 mg/kg doses in 28 days in both genders showed liver necrosis and rise of liver enzymes (p-value < 0.05). Histopathological studies didn’t show any other organ toxicity in dosed up to 1000 mg/kg. At the same time this study showed for the first the antihyperlipidemic properties of the aerial extract of Acroptilin in mice model. The pharmacological and histopathological results of the present study proved that the total parts of Acroptilon repens could be studied for supporting the traditional assertion in folk medicine to heal hyperlipidemia, diabetes, and cancer in lower doses although we performed the present study and concluded liver toxicity by subchronic use of Acropitolon repens extract.
PMCID: PMC5610761
Asteraceae Centaurea repens L; Acroptilon repens; Rhaponticum repens; Russian knapweed; Liver toxicity; Asteraceae
22.  Antihyperglycemic Effect of Rosa Damascena is Mediated by PPAR.γ Gene Expression in Animal Model of Insulin Resistance 
Insulin resistance is a condition in which insulin signaling and action are impaired in insulin sensitive tissues and result in hyperglycemia, hyperlipidemia, and type 2 diabetes mellitus. Our previous studies have shown that Rosa damascena has antihyperglycemic effects on diabetic and normal rats. Therefore, we conducted a study to evaluate the effect of this medicinal plant on insulin sensitivity in rats. This study was performed on high fructose diet insulin resistant rats and pioglitazone, an insulin sensitizing drug, was used as a positive control. Insulin resistance was developed in animals by high fructose diet within six weeks. Then, Rosa damascena extract and pioglitazone were administered by gavage for two weeks and results were compared with two control groups. After treatment period, serum glucose, insulin, adiponectin, triglyceride, and cholesterol were assayed in fasting state. Plasma free fatty acid profile was analyzed by GC. Liver PPAR.γ and muscle GLUT.4 gene expressions were assessed by real time PCR and western blotting. Animals were treated with rosa damascena extract showed levels of insulin (42 ± 2.7 pmol/L). adiponectin (5.6±0.17 μg/mL). glucose (129±4.7 mg/dL). and triglyceride (75 ± 9 mg/dl) which were significantly improved as compared with control group insulin (137 ± 34 pmol/L), adiponectin (3.9±0.15 μg/mL). glucose (187±15 mg/dL). and triglycerides (217±18 mg/dL). PPARγ protein level was also significantly increased in Rosa damascene treated group. Our results demonstrated that rosa damascena extract has useful effects on insulin resistant animals and by increasing insulin sensitivity can be considered as a potential agent in control of diabetes.
PMCID: PMC5610762
Insulin resistance; Rosa damascene; Adiponectin; Pioglitazone
23.  The Evaluation and Comparing of Cytotoxic Effects of Ferula gummosa Gum, Scutellaria lindbergii, Kelussia odoratissima and Artemisia kopetdaghensis Extracts on ACHN Cell Line 
Renal cell carcinoma (RCC) is one of most fatal cancers. In most patients it is resistant to chemotherapy. Ferula gummosa gum, Scutellaria lindbergii, Kelussia odoratissima, and Artemisia kopetdaghensis are herbs about which there are some cytotoxic activity reports. In this study, cytotoxic and apoptotic activity of these four extracts on RCC cell line (ACHN) were evaluated and compared (ACHN) cells were treated with different concentrations of herbal extracts (15-500 μg/mL). Cell proliferation was determined after 24, 48, and 72 h. by MTT assay. Apoptotic cells were determined using PI staining of DNA fragmentation by flow cytometry. Cell viability decreased with all herbal extracts in ACHN cells by 24, 48, and 72 h. as compared with control. Extracts induced a sub-G1 peak in flow cytometry histogram of treated cells indicating apoptotic cell death is involved in extracts induced-toxicity. Results imply that four herbal extracts inhibit the growth of ACHN cells as a concentration- and time-dependent manner. Also, results show that apoptosis is proposed as the possible mechanism of action. So, four herbal extracts could be considered as good anticancer agents in RCC after further studies.
PMCID: PMC5610764
Apoptosis; Cytotoxicity; Ferula gummosa gum; Scutellaria lindbergii; Kelussia odoratissima; Artemisia kopetdaghensis
24.  Exposing the Molecular Screening Method of Indonesian Natural Products Derivate as Drug Candidates for Cervical Cancer 
The menace of cervical cancer has reached an alarming rate. There are more than 450.000 cases of cervical cancer yearly, with mortality rate of about 50%. This deadly cancer is caused by human papillomavirus (HPV), mainly subtypes 16 and 18. The pharmaceutical industry has produced drug for combating the virus, known as SAHA (suberoylanilide hydroxamic acid). It inhibits class II HDAC Homo sapiens (HDACi). The utilization of SAHA has some side effects, one of which is bone loss. Thus, searching for viable alternatives aside SAHA is inevitable. The objective of this research is to investigate the molecular interaction of selected Indonesian natural products with class II HDAC Homo sapiens. LigX tool in MOE 2008.10 was used as an instrument to investigate the molecular interaction. Then, computer-aided drug discovery and development (CADDD) approach involving molecular docking and dynamics methods was utilized to screen the natural products library. In the end, we found that herbaric acid could act as a potential drug candidate for cervical cancer.
PMCID: PMC5610765
Cervical cancer; Human papillomavirus (HPV); Indonesian natural products; HDAC; HDACi; CADDD approach; Herbaric acid
25.  Single Step Purification of Novel Thermostable and Chelator Resistant Amylase from Bacillus Licheniformis RM44 by Affinity Chromatography 
Bacillus licheniformis RM44 was isolated from hot spring near Karachi and screened for the production of extracellular amylase Amy RM44. Amy RM44 was purified to homogeneity on a single step by affinity chromatography using insoluble corn starch. The molecular weight of Amy RM44 was estimated to be 66 kDa by SDS–PAGE and zymographic analysis. Nine fold purification was achieved with the specific activity of 870 U/mg that provides the total yield of the enzyme up to 31%. Studies on purified AmyRM44 characterization revealed that the optimum temperature of enzyme was 100 ºC. Amy RM44 was proved to be highly thermostable as it retained 50% activity after 2 h at 100 ºC. Amy RM44 was stable over wide range of pH with optimum activity at pH 5. Enzyme activity was not significantly inhibited by SDS and EDTA. Amy RM44 also exhibited its activity towards various carbohydrates such as dextrin, pullulan, α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin.
PMCID: PMC5610767
Amylase; Affinity chromatography; Thermostable; Chelator resistant; SDS-resistant

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