Iranian Journal of Pharmaceutical Research
Volume:17 Issue: 1, Winter 2018

Tamoxifen is routinely used for treatment of Estrogen-positive breast carcinoma. Approximately, 50% of patients with metastatic cancer will develop resistance to Tamoxifen. In this research, Tamoxifen was combined with the anti-cancer compound Curcumin. Diblock nanopolymer was used to package the new formulation of Curcumin and Tamoxifen. Anti-cancer efficacy of the obtained compound was evaluated in Tamoxifen-sensitive (TS) MCF-7, Tamoxifen-resistant (TR) MCF-7 cancer cells and Fibroblast cells. MTT assay was used to evaluate anti-proliferation and toxicity. Flow cytometry and Annexin-V-FLUOS were used to assay anti-proliferation and induction of apoptosis respectively. Our results indicate that the obtained nano-compound is less toxic to normal cells compared with Tamoxifen alone, and has higher anti-proliferation and pro-apoptotic activity on TS-MCF-7 and TR-MCF-7. The nanopolymer reduces the Tamoxifen toxicity in normal cells and counters the developed resistance to the drug in cancer cells.

Resistance to aspirin and its cytotoxicity significantly limits its therapeutic applications. Nano-liposomal encapsulation of aspirin can reduce its cytotoxicity. In this study, aspirin encapsulated nano-liposomes (AS-NL) was prepared and its performance in drug delivery and cytotoxicity was evaluated. The effects of two independent variables including: number of freeze/thawing cycles and concentration of aspirin on encapsulation efficiency was investigated using response surface methodology (RSM). A drug profile release was obtained by AS-NL. The concentration of cholesterol as effective for liposome stability and sodium lauryl sulfate (SLS) as a drug release facilitator was also optimized using RSM. The maximum aspirin encapsulation efficiency (41.44 %) and drug release (33.92 %) was obtained for 0.514 mg cholesterol and 0.007 mg SLS used for liposome formulation. The morphology and size of AS-NLs were characterized using transmission electron microscopy (TEM) and dynamic light scattering (DLS). The stability of AS-NL was evaluated by measuring the size change of nano-liposomes during 21 days using DLS analysis. The stability of AS-NL during this period was acceptable. The cytotoxicity test of AS-NL by MTT test reveals the cytotoxicity of aspirin can be reduced by using liposome encapsulation.

Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), showed very promising neuroprotection action, but it suffers from high first pass metabolism and limited ability to cross blood brain barrier. Severe gastric toxicity following oral administration further limits its utility. Hence, the aim of this study was to investigate whether ibuprofen loaded mucoadhesive microemulsion (MMEI) could enhance the brain uptake and could also protect the dopaminergic neurons from MPTP-mediated neural inflammation. In this work, ibuprofen loaded polycarbophil based mucoadhesive microemulsion (MMEI) was developed by using response surface methodology (RSM). Male C57BL/6 mice were intranasally given 2.86 mg ibuprofen/kg/day for 2 consecutive weeks, which were pre-treated with four MPTP injections (20 mg/kg of body weight) at 2 h interval by intraperitoneal route and immunohistochemistry was performed. Globule size of optimal MMEI was 46.73 nm ± 3.11 with PdI value as 0.201 ± 0.19. Histological observation showed that optimal MMEI was biocompatible and suitable for nasal application. The result showed very significant effect (p

The aim of the present study was to formulate β-cyclodextrin (β-CD) nanoparticles loaded with geraniol (GR) essential oil (EO) with appropriate physicochemical properties. Complexation of GR with β-CD was optimized by evaluation of four formulations, using the co-precipitation method, and the encapsulation efficiency (EE), loading, size, particle size distribution (PDI) and zeta potential were investigated. Further characterization was performed with nuclear magnetic resonance spectroscopy (1H NMR), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and infra-red (IR) spectroscopy analysis. Results showed that the physicochemical properties of the nanoparticles were affected by GR content in formulations that yielded nanoscale-size particles ranging from 111 to 258 nm. The highest encapsulation efficiency (79.4 ± 5.4 %) was obtained when the molar ratio of EO to β-CD was 0.44: 0.13 with negative zeta potential (-21.1± 0.5 mV). The 1H-NMR spectrum confirmed the formation structure of the EO and β-CD nanoparticle complex. Complexation with geraniol resulted in changes of IR profile, NMR chemical shifts, DSC properties and SEM of β-cyclodextrin. Inclusion complex of essential oil with β-cyclodextrin considered as promising bioactive materials for designing functional food.

A simple and selective carbon paste electrode has been developed for the electrochemical determination of acyclovir (ACV). This electrode was designed by incorporation of multiwalled carbon nanotubes (MWCNTs) and ZnO nanoparticles into the carbon paste matrix, and then poly (o-aminophenol; OAP) film were subsequently electropolymerized on it. The surface structure of nanoparticles were characterized by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Surface morphology and electrochemical properties of the prepared nanocomposite modified electrode were investigated by SEM and cyclic voltammetry (CV). The calibration graph was linear over the concentration range 0.089 to 7.96 μg mL-1 for ACV determination with a detection limit of 0.067 μg mL-1. The proposed electrode was successfully applied for ACV determination in pharmaceutical formulations with satisfactory results.

Insulin hormone is an important part of the endocrine system. It contains two polypeptide chains and plays a pivotal role in regulating carbohydrate metabolism. Insulin receptors (IR) located on cell surface interacts with insulin to control the intake of glucose. Although several studies have tried to clarify the interaction between insulin and its receptor, the mechanism of this interaction remains elusive because of the receptor’s structural complexity and structural changes during the interaction. In this work, we tried to fractionate the interactions. Therefore, sequential docking method utilization of HADDOCK was used to achieve the mentioned goal, so the following processes were done: the first, two pdb files of IR i.e., 3LOH and 3W11 were concatenated using modeller. The second, flexible regions of IR were predicted by HingeProt. Output files resulting from HingeProt were uploaded into HADDOCK. Our results predict new salt bridges in the complex and emphasize on the role of salt bridges to maintain an inverted V structure of IR. Having an inverted V structure leads to activate intracellular signaling pathway. In addition to presence salt bridges to form a convenient structure of IR, the importance of α-chain of carboxyl terminal (α-CT) to interact with insulin was surveyed and also foretokened new insulin/IR contacts, particularly at site 2 (rigid parts 2 and 3). Finally, several conformational changes in residues Asn711 - Val715 of α-CT were occurred, we suggest that α-CT is a suitable situation relative to insulin due to these conformational alterations.

In this investigation, the synthesis of 2-substituted pyrimidines by the reaction of benzofuran chalcones (3a-d) with urea, thiourea and guanidine hydrochloride was reported. The structures of title compounds (4a-d), (5a-d) and (6a-d) were established on the basis of analytical and spectral data. The synthesized compounds were screened for antimicrobial activity and molecular docking studies. Some of the compounds displayed excellent antimicrobial activity. The molecular docking analysis revealed that compounds 5a and 5c with the lowest binding energy in comparison to others suggesting its potential as best inhibitor of GluN-6 P. Consequently, it is confirmed from the above analysis that the compounds 5a and 5c might serve as a useful backbone scaffold for rational design, adaptation and investigation of more active analogs as potential broad spectrum antimicrobial agents.

A new series of peptide-like derivatives containing different aromatic amino acids and possessing pharmacophores of COX-2 inhibitors as SO2Me or N3 attached to the para position of an end phenyl ring was synthesized for evaluation as selective cyclooxygenase-2 (COX 2) inhibitors. The synthetic reactions were based on the solid phase peptide synthesis method using Wang resin. One of the analogues, i.e., compound 2d, as the representative of these series was recognized as the most effective and the highest selective COX-2 inhibitor with IC50 value of 0.08 μM and COX-2 selectivity index of 351.2, among the other synthesized compounds. Molecular docking study was operated to determine possible binding models of compound 2d to COX-2 enzyme. The study showed that the p-azido-phenyl fragment of 2d occupied inside the secondary COX-2 binding site (Arg513, and His90). The structure-activity relationships acquired disclosed that compound 2d with 4-(azido phenyl) group as pharmacophore and histidine as amino acid gives the essential geometry to provide inhibition of the COX-2 enzyme with high selectivity. Compound 2d can be a good candidate for the development of new hits of COX-2 inhibitors.

The interest in the synthesis of metallic complexes of different drugs to make them more efficient in biological environment of the human body is seen for the last few decades. Wide range of metal complexes are already used in clinical practice which encourages additional research for innovating new metal based drugs, such as metal-mediated antibiotics, antiparasitic, antiviral, antibacterial, and anticancer compounds. Tuberculosis has been known as one of the most disastrous disease putting burden on health system worldwide. Though the therapeutic agents to combat the disease are well practiced, emergence of multi drug resistant strains makes the treatment strategies more difficult. The following work aims to synthesize copper, ferrous, ferric, cobalt and manganese complexes of renowned anti tuberculosis drug, pyrazinamide (PZ). These compounds were tested for anti-tuberculosis using five multidrug resistant strain of Mycobacterium tuberculosis. For this purpose BACTEC MGIT 960 system was used. The drug PZ was also screened with the synthesized complexes. The two complexes of cobalt and manganese proved potent among all of the compounds tested.

In this study, the existence of biological potential of selected N-(substituted phenyl)-2- chloroacetamides was examined none empirically, as was the possibility of applying simple experimental technique in predicting essential properties which affect the biological activity of the compounds. By applying the Lipinski and Ghose’s rules, it has been revealed that the examined chloroacetamides fulfill the theoretical requirements for bioactive compounds. In addition, lipophilicity was determined by applying the reversed-phase thin-layer chromatography (RPTLC18F254s) in the mixtures of water and two organic modifiers separately (methanol and acetone) and by using relevant software packages. The chromatographic retention parameters, RM 0 and m, as the presumed criteria for the lipophilicity of the examined chloroacetamides were correlated by linear regression analysis, and the relevant chemometric methods (Cluster Analysis and Principal Component Analysis) with the standard measure of lipophilicity, log P, and with the selected pharmacokinetic predictors. Thus good correlations in both water-modifier systems (average correlation coefficients, r , 0.947 and 0.931) were obtained. The chemometric methods, as well as the classical correlation methods gave similar results which demonstrated that the chromatographic retention parameters, RM 0 and m, can successfully describe the lipophilicity and the pharmacokinetics of the N-(substituted phenyl)- 2-chloroacetamides in the first steps of preclinical research.

Nonsteroidal anti-inflammatory drugs (NSAIDs) act mainly via inhibition of prostaglandins synthesis by inhibition of cyclooxygenase (COX) isoenzymes (COX1 and COX 2). Selective COX-2 inhibitors which are also known as coxibs provide the main therapeutic effects of NSAIDs. Zarghi et al. reported 6-benzoyl-2-(4-(methylsulfonyl)phenyl)quinoline-4-carboxylic acid (AZGH 101) as a novel derivative of ketoprofen with improved selectivity index (COX-1/COX-2 inhibitory potency) in comparison with ketoprofen.
In this study the log P and stability of AZGH 101 was evaluated and the pharmacokinetic characteristics of this compound were investigated following intravenous (10 mg/kg), and oral administration (20 mg/kg), to Wistar rats.
As the data demonstrated the AZGH 101 classified as lipid soluble compound and had suitable stability according to forced degradation protocol ICH guideline for new drug substance. This derivative absorbs, distributes and eliminates similar in both sexes. The AUC 0-∞, absolute bioavailability, Cl and Vd were not different in both sexes.
According to the obtained data the AZGH 101 has not a sex dependent pharmacokinetic in Wistar rats.

In communities which consume rice as main food, importance of risk assessment for contaminants is always taken into consideration by health authorities. The present study is an attempt for monitoring of 56 pesticides from different chemical groups in rice samples collected from local markets in Tehran and estimation of daily intake of interested pesticides through this monitoring. A valid method based on spiked calibration curves and QuEChERS sample preparation was developed for determination of pesticides residue in rice by GC/MS. The analytical results of the proposed method were in good agreement with the proficiency test (FAPAS 0969). One-hundred-thirty-five rice samples were analyzed and 11 pesticide residues were found in 10.4% of the samples. Of which 5.2% were contaminated with unregulated pesticides. None of the samples, which were contaminated with regulated pesticides, had contamination higher than maximum residue limit. The mean estimated dose (ED) was calculated with respect of mean of contamination and mean daily consumption of rice. ED of the found pesticides is much lower than the related ADIs.

Ochratoxin A (OTA) is one of the most important mycotoxins that contaminate a broad range of agricultural and food products. In this study, the occurrence of OTA in available brands of grape juice in Iran purchased from retail outlets or producer were determined for the first time using high-performance liquid chromatography (HPLC) with immunoaffinity columns(IAC) as the clean-up step. The average recoveries for OTA in grape juice ranged from 54.2 to 86.6 % with the coefficient of variation lower than 17.3% in lowest spiked level (0.5 µg/L).The estimated LOD and LOQ of OTA were 0.04 µg/L and 0.125 µg/L, respectively. In our study, 70 samples of grape juice evaluated for OTA content. The results showed that in 39 out of 70 samples (55.7%) OTA levels were above the LOQ with the maximum level of 2.6 µg/L and the mean contamination was 0.5 µg/L. Although the mean contamination of OTA in analyzing samples was lower than the MRL set by EU, the high incidence of contamination in this products is worried. Considering the importance of OTA in public health, control of pre- and post-harvest, storage and grape juice manufacturing process, such as HACCP and GAP and GMP recommended preventive measures are required.

Cisplatin is one of the most useful chemotherapeutics which performs its cytotoxic effect via accumulation of platinum resulting in oxidative stress, and destruction of cell DNA. This could probably cause secondary cancers in healthy tissues. Lipocalin2 (Lcn2) is a protein which its expression is increased in oxidative stresses. Therefore, the present study was performed to evaluate the protective effects of Lcn2 up-regulation on cisplatin genotoxicity. In order to up-regulate Lcn2 expression, HEK293 cells were transfected with pcDNA3.1-Lcn2 vector. Afterwards, stable cells consistently expressing Lcn2 were selected via screening with 418 antibiotic. Next, overexpression of Lcn2 was evaluated by RT-PCR and ELISA, comparing to the control non-transfected cells. Then, in order to evaluate the cytoprotective effects of Lcn2 overexpression, transfected and non-transfected cells were subjected to cisplatin treatment followed by MTT and alkaline Comet assays. RT-PCR and ELISA assays confirmed upregulation of Lcn2 by the stable cells. MTT assay of the Lcn2 over-expressing cells showed higher IC50 values comparing to the non-transfected cells. Furthermore, the Comet assay confirmed Lcn2 protective effects on the cisplatin (1 μg/mL) induced genotoxicity. In the present study, for the first time, we showed the protective effect of Lcn2 on cisplatin induced genotoxicity. Therefore, one of the probable mechanisms of Lcn2 cytoprotctive effects under oxidative stress conditions could be due to the prevention of genotoxicity. However, further evaluations in this regard must be considered.

Selective COX-2 inhibitors are most widely used analgesic and anti-inflammatory drugs; however, its maximal use is highly associated with various serious abnormal cardiovascular events. Beraprost sodium (BPS), prostacyclin analogue has been shown to vasodilatory, antiplatelates, anti-inflmmatory, and antioxidant activity. The objective of the present study was to evaluate the effect of BPS on celecoxib cardiotoxicity in rats. Toxicity was induced in male Albino rats (250-280 g) by celecoxib (100 mg/kg/day). BPS (30 μg/kg/day) was administered alone and in combination with celecoxib for 14 days and various biochemicals, hemodynamic, left ventricular, biochemical, and histopathological parameters were studied. Cardiotoxicity of celecoxib was revealed by a significant increase in serum lactate dehydrogenase (LDH), troponin-T (Tn-T), tumor necrosis factor-α (TNF- α), creatine kinase-MB (CK-MB) and systolic blood pressure (SBP), left ventricular end diastolic pressure (LVEDP), LV (dp/ dt)max, and LV (dp/dt)min as well as tissue thiobarbituric acid reactive substance (TBARS) and a significant decrease in tissue reduced glutathione (GSH). However, treatment with BPS reversed these alteration in LDH, Tn-T, TNF-α, CK-MB, SBP, LVEDP, LV (dp/dt)max, LV (dp/dt)min, TBARS and GSH levels. The histopathological study in cardiac left ventricle revealed protection of myocardium as manifested reduction of fibrosis by abolition of collagen deposition when celecoxib was combined with beraprost sodium. It could be concluded that beraprost sodium may prove a useful adjunct in patients being prescribed celecoxib.

Obesity is a main reason of type 2 diabetes and also chronic exposure to arsenic (As) can produce diabetic symptoms. In previous studies, the association between high-fat diet and arsenic in the incidence of diabetes was found, but the role of beta cells activity, liver mitochondrial oxidative stress, and hepatic enzymes (leptin, adiponectin and beta amylase) was unclear. Thus, present study was conducted to evaluate the diabetogenic mechanism of arsenic followed by concomitant administration of high-fat diet (HFD) in male mice. In this experimental study, the mice consumed with HFD or low-fat diet (LFD) while exposed to As 25 or 50 ppm in drinking water for 20 weeks. At the end of experiments, hyperglycemia, insulin resistance variables, lipid profile, hepatic enzymes, liver mitochondrial oxidative stress, islet insulin secretion, liver, and pancreas histopathology were evaluated in all mice by their own methods. Control HFD fed mice showed a significant increase in FBG, OGTT, HOMAIR, ITT, lipid profile, leptin, β-amylase, liver mitochondrial oxidative stress, hepatic enzymes and decreased FPI, HOMA-β, adiponectin, and islet insulin secretion or content. However, exposure to HFD concomitant with Arsenic revealed an impressive reduction in FBG, FPI, HOMA-IR, HOMA-β, ITT, lipid profile, and islet insulin secretion or content. This exposure enhanced OGTT, leptin, adiponectin, liver mitochondrial oxidative stress, and hepatic enzymes. In conclusion, HFD and arsenic concomitant administration induced impairment of OGTT and islet insulin secretion or content through the mitochondrial oxidative stress.

Bothutous Schach (BS) scorpion venom consists of several polypeptides that could modulate ion channels. In this study, the effects of BS crude venom on passive and active electrophysiological properties of rat neurons in supraoptic nucleus (SON) of hypothalamus was investigated using whole-cell patch clamp technique. The results showed that bath application of BS venom produced significant change in passive properties of SON neurons, namely a decrease in resting membrane potential and an increase in input resistance of the cells. Also, significant change in active properties of SON neurons was shown after bath application of BS venom; including a decrease in the number of evoked action potential along with an increase in half width and decay time of action potential and a significant decrease in afterhyperpolarization amplitude. Finally, a decreased latency to the first spike accompanied by a lower current threshold to elicit the first spike was shown compared with the values before venom application. These effects are possibly through blocking different ion channels including potassium channels. Further experiments using different fractions of the venom is required to specify venom effects on various ion channels.

DHIPC (2,4-dichloro-2´-hydroxyl-4´,6´-diisoprenyloxychalcone) is a new chalcone compound. In this study, its antidepressant-like activity of compound DHIPC was evaluated by the forced swimming test and the tail suspension test in mice. The results showed that DHIPC significantly reduced the immobility time for 2 h after treatment through the oral administration at dose of 10, 20, and 30 mg/kg in the forced swimming test and the tail suspension test, indicating a significant antidepressant-like effect. The maximal effect was obtained at 30 mg/ kg, which is similar to the positive control fluoxetine. The main monoamine neurotransmitters and their metabolites in rat brain were also simultaneously determined. It was found that DHIPC significantly increased the concentrations of the main neurotransmitters serotonin and noradrenalin, and also significantly increased 5-hydroxyindoleacetic acid contents in hippocampus, hypothalamus, and cortex in brain part. So, the probable mechanism of action of DHIPC is thought to be related to increase in serotonin and noradrenalin in the brain.

The current study was carried out to evaluate the in-vitro and in-vivo efficiency of alpha glucosidase inhibitor of marine actinobacteria in the control of postprandial hyperglycaemia. Soil samples were collected from salterns, coastal area in Kothapatnam, Ongole, Andhra Pradesh, India. Among the actinobacterial isolates tested for yeastα-glucosidase inhibitory activity, only three isolates showed prominent inhibition. The patient isolate was selected and identified as Streptomyces coelicoflavus SRBVIT13 using 16S r-RNA gene sequencing. In in-vitro studies, the chloroform extract of Streptomyces coelicoflavus SRBVIT13 showed significant enzyme inhibitory activity against yeast and mammalian α-glucosidaseenzymes. In animal studies, the oral ingestion of chloroform extract (600 mg/kg) of S. coelicoflavus SRBVIT13 in maltose and sucrose loaded diabetic rats, showed significant regulation of postprandial blood glucose by 82.25% and a 77.25% reduction, respectively. The lead compound from S. coelicoflavusSRBVIT13 was isolated, purified, characterized, and identified by stranded analytical techniques as 2-t-butyl-5-chloromethyl-3-methyl-4-oxoimidazolidine- 1-carboxylic acid, t-butyl ester. The results obtained in the present study are promising and the bioactive compound from S. coelicoflavusSRBVIT13 may be considered as a potential agent in regulating the postprandial hyperglycaemia.

Aims:Memory deficit is the most visible symptom of cerebral ischemia. The hippocampus is sensitive against cerebral ischemia. Oxidative stress and inflammation are involved in the pathological process after cerebral ischemic injury. Paroxetine has anti-oxidative and anti-inflammatory effects. In this study the effect of paroxetine on memory deficit after cerebral ischemia was investigated.
Cerebral ischemia/reperfusion (I/R) injury model was established using the bilateral occlusion of common carotid artery method. Paroxetine (10 mg/kg) was intraperitoneally injected into rats, 24 hours before surgery or once a day for 7 days after surgery. Learning and memory were evaluated using the Morris water maze task, then the brain tissue was fixed and hippocampal CA1 pyramidal cells damage was analyzed using the Nissl staining method.
In the ischemia group the escape latency time (ELT) and the swimming path length (SPL) were significantly increased and the time spent in target quadrant (TSTQ) was significantly decreased compared with the control group. The ELT and the SPL were significantly shortened and the TSTQ was significantly increased compared with the ischemia group after Pre- or post-ischemic administration of paroxetine. The percentage of viable pyramidal cells in the ischemia group was significantly decreased compared with the control group. The percentage of viable cells was significantly increased following pre-or post-ischemic administration of paroxetine compared with the ischemia group.
Memory deficit due to I/R was improved and the percentage of viable cells in CA1 region was increased after administration of paroxetine. Therefore, paroxetine may have a neuroprotective effect against cerebral ischemia.

Nepeta (Lamiaceae) is an important genus with beneficial medicinal properties. N. sintenisii Bornm. has been used in folk medicine of Iran to cure various diseases. We investigated the anti-melanogenesis effects of n-hexane, MeOH, CH2Cl2, n-BuOH, EtOAc, and H2O extracts isolated from the plant in B16 melanoma cells. Various assays including cytotoxicity, mushroom tyrosinase inhibition, inhibition of cellular tyrosinase, melanin content, the amount of reactive oxygen species and western blotting were done to assess the plant activities on melanogenesis inhibition. All extracts of N. sintenisii could significantly reduce both tyrosinase activity and the cellular melanin content. Reactive oxygen species were also significantly decreased following the treatment of cell with n-BuOH and EtOAc extracts with no cytotoxicity. The plant significantly decreased the amount of microphthalmia-associated transcription factor proteins. Collectively, N. sintenisii inhibited melanin synthesis and tyrosinase activity in B16 melanoma cells with no cytotoxic effects. Hence, it might merit further investigations for elucidation of anti-hyperpigmentation agents.

Eysenhardtia polystachya is widely used in folk medicine as an anti-rheumatic and analgesic agent, but no systematic study of its effects on several markers associated with rheumatoid arthritis and its ethnomedical use as analgesic agent has been performed. We evaluated the anti-arthritic and antinociceptive properties of an ethanolic extract of E. polystachya (EE) bark and its rich-flavonoids fractions in murine models. The EE was administered orally at doses of 25, 50, 100, and 200 mg/kg/day, and its fractions at 25 mg/kg/day in all animal models. Antiarthritic activity was evaluated using a complete Freund´s adjuvant (CFA)-induced rheumatoid arthritis model in rats. The severity of arthritis was evaluated by changes in paw oedema, body weight, arthritic index, radiological scores, histological assessment of synovial joints, erythrocyte sedimentation rate, haematocrit, haemoglobin, serum rheumatoid factor, serum C-reactive protein and serum levels of the pro-inflammatory cytokines IL-1β, IL-6, TNF-α, IL-18, IFN-γ, GM-CSF, and anti-inflammatory cytokines IL-4, IL-10, IL-13. Antinociceptive activity was evaluated using an acetic acid-induced abdominal contraction test and a hot-plate test in mice. EE and its rich-flavonoids fractions inhibited secondary inflammatory reactions, diminished the specific histopathological alterations in the joint capsule and reduced the serum concentrations of the pro-inflammatory cytokines IL-6, TNF-α, and GM-CSF in arthritic rats. EE also reduced the number of writhes produced by acetic acid and increased the response time on the hot plate for mice. Our findings support the use of Eysenhardtia polystachya bark for the treatment of rheumatoid arthritis and pain management.

Ginseng is now used worldwide as a traditional Oriental medicine. Ginsenosides, also known as ginseng saponins, are responsible for most pharmacological efficacies of ginseng. This work aimed to assess the novel skin anti-photoaging potential of ginsenoside Re (Re), a protopanaxatriol-type ginsenoside, by analyzing reactive oxygen species (ROS), pro-matrix metalloproteinase-2 (proMMP-2) and -9 (proMMP-9), total glutathione (GSH), superoxide dismutase (SOD), and cellular viability in UV-B-irradiated HaCaT keratinocytes. When HaCaT cells were pretreated with Re prior to UV-B irradiation, Re significantly suppressed the UVB-induced ROS elevation. It was also able to attenuate the UV-B-induced proMMP-2 and -9 elevations at both activity and protein levels. Re was capable of overcoming the UV-B-reduced total GSH content and SOD activity in concentration-dependent ways. Under the experimental conditions used, Re could interfere with cellular viabilities in neither non-irradiated nor UV-Birradiated keratinocytes.

Human hepatocellular carcinoma is one of the most common recurrent malignancies since there is no effective therapy for it. Silibinin, a widely used drug and supplement for various liver disorders, demonstrated anti-cancer effects on human hepatocellular carcinoma, human prostate adenocarcinoma cells, human breast carcinoma cells, human ectocervical carcinoma cells, and human colon cancer cells. Considering the anti-hepatotoxic activity of silibinin and its strong preventive and anti-cancer efficacy against various epithelial cancers, we investigated the efficacy of silibinin against human HCC and HUVEC cell lines. Silibinin effects on the growth and mode of cell death of these two cell lines are presented in this paper. HepG2 and HUVEC cells were incubated with different doses of silibinin (12.5, 25, 50, 100, 150 and 200 μg/mL) at 24, 48, and 72 h. Cytotoxicity was assessed using MTT and Trypan blue assays. Mode of cell death induced by silibinin was investigated using LDH assay and acridine orange/ PI double dye staining. The results showed that silibinin has dose-dependent inhibitory effect on the viability of HepG2 and HUVEC cells. However, Silibinin causes a more continuous dose-dependent cytotoxicity in HepG2 cells compared to the HUVEC cells in which some degrees of resistance is apparent at the beginning. The mode of cell death looks also different in these two cell lines with HepG2 cells being more in favor of apoptosis while necrosis is more evident for the HUVEC cells.

With the increase of neglected diseases such as leishmaniasis and Chagas disease, there was a need for the search for new therapeutic alternatives that reduce the harm caused by medicine available for treatment. Thus, this study was performed to investigate the antiparasitic activity of the essential oil from the fruits of Piper tuberculatum Jacq, against lines of Leishmania braziliensis (MHOM/CO/88/UA301), Leishmania infantum (MHOM/ES/92/BCN83) and Trypanosoma cruzi (LC-B5 clone). Before running protocols, an analysis of the chemical composition of essential oil was conducted, which presented monoterpenes and sesquiterpenes. As major constituents, β-pinene and α-pinene were identified. Regarding to antiparasitic activity, the essential oil had an EC50 values of 133.97 µg/mL and 143.59 µg/mL against variations promastigotes of L. infantum and L. braziliensis, respectively. As for trypanocidal activity, the oil showed EC50 value of 140.31 µg/mL against epimastigote form of T. cruzi. Moreover, it showed moderate cytotoxicity in fibroblasts with LC50 value of 204.71 µg/mL. The observed effect may be related to the presence of terpenes contained in the essential oil, since it has its antiparasitic activity proven in the literature.

Viola odorata as a medical herb is used in liver disorders and relieving cancer pain. In the present study, the cytotoxic, antioxidant, and anti-metastatic properties of Viola odorata hydroalcoholic extract (VOE) were investigated in 4T1 breast cancer model. After treatment of 4T1 breast cancer cells with VOE, cell viability was measured by MTT assay. The implanted mice were treated with different concentration of VOE (50, 150 and 250 mg/kg) for 21 days. Levels of lactate dehydrogenase (LDH), γ -glutamyl transferase (GGT), alkaline phosphatase (ALP), carcinoembryonic antigen (CEA) and cancer antigen 15-3(CA15-3) in serum, and also catalase (CAT) and superoxide dismutase (SOD) activities in tumor tissue were measured. Metastatic rate was investigated in liver, spleen and lung tissues. VOE decreased cell viability of 4T1 cells, significantly. VOE significantly inhibited the cell proliferation, but not vasculature in the tumors that revealed by immunohistochemical analysis for Ki-67 and CD31 expression, respectively. VOE increased the Bax/Bcl-2 ratio in VOE250-treated group compared to control group. Serum analysis showed that treatment with 250 mg/kg of VOE significantly reduced LDH (not ALP and GGT) levels compared to controls. No linear correlation was found between the values of CEA and CA15-3 with tumor size. The rate of CAT activity was increased in VOE250-treated rats whereas, CAT and SOD activities were reduced in VOE50 group. VOE250 significantly decreased the metastatic rate in liver and lung compared to the other doses of VOE. Consequently, Viola odorata has cytotoxic effects on 4T1 cells and affects antioxidant activity and metastasis in breast cancer.

The anti-hypercholesterolemic effect of berbamine (BBM) isolated from Rhizoma Coptidis (RC) was investigated in hypercholesterolemic zebrafish model induced by high-cholesterol (HC) diet. Zebrafish embryo assay revealed no significant difference in morphology and cell death with the treatment of BBM less than 20 μg/mL. In zebrafish larvae, the fluorescently labeled cholesterol in caudal artery was reduced dose-dependently after BBM treatment. For adult zebrafish, administration of 0.2% BBM exhibited a significant decrease in plasma total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-c) levels by 37%, 38% and 28%, respectively, along with a fall in lipid content in liver. Further investigation suggested that the mRNA expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and microsomal triglyceride transfer protein (MTP) in liver were downregulated and the transcription levels of liver gene low-density lipoprotein receptor (LDLR) and cytochrome P450 polypeptide 1a of subfamily A of family 7 (CYP7A1a) were significantly up-regulated with BBM treatment. Histological study showed that BBM can alleviate hepatic steatosis induced by HC diet. These data suggested that BBM has anti-hypercholesterolemic and hepatoprotective effects. The mechanism probably related to the up-regulation of cholesterol transport and bile acid synthesis as well as inhibition of cholesterol synthesis and lipoprotein assembly or secretion.

The aim of the present study was to determine cytotoxic activity of crude methanolic extract of Echinophora platyloba on breast cancer MDA-MB-231 cell line. The free radical scavenging effects of methanolic extract of E. platyloba were tested using DPPH method. Crude methanolic extract exhibited potential antioxidant activity with an IC50 value of 234.28 ± 21.63 μg/mL when compared to the standard BHT with an IC50 value of the 19.5 ± 0.8 μg/mL. In addition, the in-vitro cytotoxic activity of this extract was studied against MDA-MB-231 and MCF-10a cells by MTT assay for 12, 24 and 36 h. Our data showed 534.6 ± 7.2 μg/mL of extract following 24 h of incubation was the most cytotoxic dose against MDA-MB-231 cells in comparison with other doses. This extract could induce apoptosis and promote cell-cycle arrest at S-phase in MDA-MB-231 cells after 24 h of incubation, as compared to the control group (p

The genus Achillea (Asteraceae) consisting of important medicinal species, growing wildly in Iran, of which A. tenuifolia is found in Iran-o-Turan regions. Regarding the traditional use of Achillea species for treatment of diabetes and also lack of information on phyto-constituents of A. tenuifolia underground parts, in this study anti-diabetic activity of the plant have been reported. In order to find the main active components, underground parts of the plant were extracted with water and fractioned by hexane, ethyl acetate, and methanol and the separation of the main compounds were carried out via medium pressure liquid chromatography (MPLC). Also, anti-diabetic effects of the extract were investigated on rat pancreatic islets. The root extract of the plant as well as the compound β-sitosterol showed moderate α-amylase inhibitory activity, however prangol did not suppress the enzyme activity. The results of islet cells’ biofunction assays revealed that the herb root extract was able to increase the secretion of insulin in high concentration (10 mg/mL) and improved the cell viability with no toxicity in all doses. Furthermore, the herbal extract could reduce the levels of reactive oxygen species (ROS) and lipid peroxidation (LPO). The plant extract also significantly decreased the enzyme activity for both caspase-3 and -9 and increased the antioxidant capacity of the isolated cells. Taking together, preparations or extracts from the underground parts of the plant are good candidates for further anti-diabetic investigation and clinical trials.

In this study, the mutagenic and anti-mutagenic effects of methanol extract of three lichen species (Cetraria aculeata, Cladonia chlorophaea and Cetrelia olivetorum) were investigated by using E. coli-WP2, Ames-Salmonella (TA1535 and TA1537) and sister chromatid exchange (SCE) test systems. The results obtained from bacterial test systems demonstrated that methanol extracts of three lichen species have strong anti-mutagenic potencies on TA1535, TA1537 strains and to a lesser extent on E. coli-WP2 strain. The anti-oxidant level of human lymphocytes cells was determined in order to clarify the mechanism underlying the anti-mutagenic effects of these lichen species. Co-treatments of 5, 10 and 20 µg/mL concentrations of these three lichen species with AFB decreased the frequencies of SCE and the level of MDA and increased the amount of SOD, GSH and GPx which decreased by aflatoxin. The findings of this work have clearly demonstrated that Cetraria aculeata, Cladonia chlorophaea and Cetrelia olivetorum have significant anti-mutagenic effects which are thought to be partly due to the anti-oxidant activities and the interaction capability of lichen extracts with mutagen agents (Sodium azide, acridin, N-methyl-N′-nitro-N-nitrosoguanidine and aflatoxin B1).

In this research, aerial parts of Euphorbia denticulata Lam were collected from Sanandaj city in Kurdistan province at the West of Iran. It was extracted by maceration using acetone as solvent. The isolation of compounds were carried out with repeated column chromatography using silica gel and normal preparative HPLC using YMC-Pack-Sil column and hexane: ethyl acetate as mobile phase. The structures of isolated compounds were elucidated by extensive 1 and 2D-NMR as well as HRESI-MS spectra and the cytotoxicity was done against DU-145 human prostate cancer cell line using standard MTT assay. It afforded a new 12-taraxastane derivative and two known cycloartane triterpenes including: taraxast-12-ene-3β,20,21(α)-triol (1), cycloartane-3β,25-diol (2), and cycloartane-3β,24,25-triol (3). They exhibited cytotoxic effects, with IC50 values of 12.2 ± 2.9, 27.5 ± 4.9, and 18.3 ± 1.4 µM, respectively.

Satureja khuzestanica Jamzad (Marzeh Khuzestani in Persian) is an endemic plant that is widely distributed in the southern part of Iran. Despite the number of papers published on this plant, no one has focused on its anticancer effects. Therefore, the present study was designed to investigate the selective cytotoxic and anti-proliferative properties of satureja khuzestanica total extract (SKE). MCF-7 human breast cancer cells were used in this study. Cytotoxicity of the extract was determined using MTT and neutral red assaysafter 24 h treatment period. Biochemical markers of apoptosis (caspase-3, Bax, Bcl-2) and cell proliferation (cyclin D1) were evaluated by immunoblotting. Vincristine was used to evaluate the synergic effect of extract with an anticancer drug. The data showed that treatment of cells with SKE (150 and 200 µg/mL for 24 h) significantly reduced cell viability, activated caspase 3 and increased Bax/Bcl2 ratio. In addition, cyclin D1 expression was significantly decreased in the SKE-treated cells. In addition, concomitant treatment of the MCF-7 cells with SKE and vincristine produced a potent anti-proliferative and pro-apoptotic effect compared to extract or drug alone. In conclusion, satureja extract has a potential anti-cancer property against human breast cancer cells and its combination with chemotherapeutic agent vincristine may induce cell death effectively and be a potent modality to treat this type of cancer.

Diabetes mellitus is a group of metabolic disorders characterized by elevated blood sugar and abnormalities in insulin secretion and action. There are many anti-diabetic plants, which might supply useful sources for developing new medicines that can be used in treatment of diabetes mellitus. The primary objective of the present investigation is to evaluate the antidiabetic properties of the aerial parts of Amygdalus lycioides in streptozocin-induced diabetic rats. Sixty rats were divided into 6 groups: streptozocin-induced diabetic control, insulintreated diabetic group, and four Amygdalus lycioides-treated diabetic groups (125, 250, 500, and 1000 mg/kg/day). After 2 weeks of plant extract administration, the effects of extracts on blood glucose, body weight, BUN, creatinine, total cholesterol, LDL, HDL, triglyceride, total protein, Na, K, and plasma enzymes (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase) were analyzed. The pancreas of rats was also stained for stereological studies. Phytochemical evaluation of this extract showed the presence of flavonoids and tannins compounds. Glucose serum levels and glucose tolerance test showed a decrease in treatment with Amygdalus lycioides (1000 mg/kg). Serum total cholesterol, LDL, triglyceride, creatinine and alkaline phosphatase levels were decreased significantly by the extract but aspartate aminotransferase found to be increased after treatment. The total number and numerical density of beta cells increased in the Amygdalus lycioides group (1000 mg/kg). It seems that Amygdalus lycioides may act as a potential drug to treat diabetes and its complications. However, more investigations should be done to more clarify these results.

The essential oils obtained by hydrodistillation from the stem, leaf and flower of Phlomis aucheri Boiss., which is endemic to Iran, stem, leaf and root of Teucrium polium L. and solvent free microwave extraction oil from leaf of Ajuga chamaecistus Ging. Subsp chamaecistus were analyzed by GC and GC/MS. Germacrene D (11.10%, 28.31% and 21. 06%) was the main constituent in the stem, leaf, and flower oils of P. aucheri, respectively. The other main component in the stem oil of the plant was (E) - anethole (24.58%) and in the flower oil was β- caryophyllene (15.93%). All three oils were rich in regard to sesquiterpenes. The main components in the stem, leaf and root of T. polium were α- muurolol (25.02%, 20.03% and 19.53%), α- cadinol (15.72%, 8.11% and 13.01%) and β-cayophyllene (10.86%, 10.11% and 10.64%) respectively. All three oils were rich in regard to sesquiterpenes. The major components in the leaf oil of A.chamaecistus were (z)-β-ocimene (12.11%) and germacrene D (10.11%). The oil of the plant was rich in regard to both monoterpens and sesquiter penes.

Cardiosphere-derived cells (CDCs) have emerged as one of the most promising stem cell types for cardiac protection and repair. Exosomes are required for the regenerative effects of human CDCs and mimic the cardioprotective benefits of CDCs such as anti-apoptotic effect in animal myocardial infarction (MI) models. Here we aimed to investigate the anti-apoptotic effect of the hypoxic and normoxic human CDCs-derived exosomes on induced apoptosis in human embryonic stem cell-derived cardiomyocytes (hESC-CMs). In this study, CDCs were cultured under normoxic (18% O2) and hypoxic (1% O2) conditions and CDC-exosomes were isolated from conditioned media by differential ultracentrifugation. Cobalt chloride as hypoxiamimetic agents at a high concentration was used to induce apoptosis in hESC-CMs. The caspase-3/7 activity was determined in apoptosis-induced hESC-CMs. The results indicated that the caspase-positive hESC-CMs were significantly decreased from 30.63 ± 1.44% (normalized against untreated cardiomyocytes) to 1.65 ± 0.1 and 1.1 ± 1.09 in the presence of normoxic exosomes (N-exo) at concentration of 25 and 50 μg/mL, respectively. Furthermore, hypoxic exosomes (H-exo) at concentration of 25 and 50 μg/mL led to 8.75 and 12.86 % reduction in caspase-positive cells, respectively. The anti-apoptotic activity of N-exo at the concentrations of 25 and 50 μg/mL was significantly higher than H-exo. These results could provide insights into optimal preparation of CDCs which would greatly influence the anti-apoptotic effect of CDC-exosomes. Totally, CDC-secreted exosomes have the potential to increase the survival of cardiomyocytes by inhibiting apoptosis. Therefore, CDC-exosomes can be developed as therapeutic strategy in ischemic cardiac disease.

The Stober process is frequently used to prepare silica-coated iron oxide nanoparticles. This is usually achieved by seeding a reaction mixture consisting of water, ethanol and a catalyst with iron oxide particles and adding a silica precursor. The hydrolysis and condensation of precursor monomers results in the deposition of a silica layer on iron oxide particles. However, this process is accompanied by an increase in the ionic strength of the medium which promotes the rapid aggregation of iron oxide particles. A number of methods have been developed to prevent seed aggregation during the coating process. The majority of these methods include a pretreatment step in which the surface of iron oxide particles is modified in a manner that increases their stability in aqueous solutions. Here we suggest that by decreasing the initial concentration of the catalyst for a short period to minimize nucleation by reducing precursor hydrolysis rate and then gradually increasing the concentration to the optimum level to allow silica formation to proceed normally it may be possible to prevent aggregation without surface modification. The properties of the resulting nanoparticles as analyzed by transmission electron microscopy and magnetometry as well as their efficiency at extracting genomic DNA from different bacterial strains compared to that of a commercial extraction kit are also reported.

Tumor-targeted therapies are playing growing roles in cancer research. The exploitation of these powerful therapeutic modalities largely depends on the discovery of tumor-targeting ligands. Phage display has proven a promising high throughput screening tool for the identification of novel specific peptides with high binding affinity to cancer cells. In the present study, we describe the use of phage display to isolate peptide ligands binding specifically to human lung cancer cells. Towards this goal, we screened a phage display library of 7-mer random peptides in-vitro on non-small cell lung carcinoma (A549) as the target cell. Following selection rounds, there was a highly considerable enrichment of lung cancer-binding phages and a significant increase – 170 fold - of the phage recovery efficiency. After three rounds of in-vitro panning, a group of peptides with different frequencies were obtained. The binding efficiency and selectivity of these peptides for target and control cells were studied. The results of cellular binding assay and cell ELISA (enzyme-linked immunosorbent assay) revealed that LCP1 (Lung Cancer Peptide1) with the displayed sequence AWRTHTP is the most effective peptide in binding to lung cancer cells compared with normal lung epithelial cells and different non-lung tumor cells. In conclusion, our findings suggest that LCP1 may represent a novel peptide that binds specifically to lung cancer cells and further studies can pave the way for its application as a potential targeting moiety in the targeted delivery of diagnostic and therapeutic agents into lung malignant cells.

Sexual dysfunction is a common cause of selective serotonin reuptake inhibitor (SSRI) withdrawal. Various studies indicate that decreased oxytocin is involved as a mechanism of delayed ejaculation induced by SSRIs. The aim of the present pilot study was to evaluate and compare sexual dysfunction and oxytocin levels in women being treated with either fluoxetine or citalopram. Thirty-nine women with the diagnosis of major depressive disorder were enrolled in the study. A baseline blood sample was collected and each participant was given either fluoxetine 20 mg/d or citalopram 20 mg/d. After 1 month, a second blood sample was collected and sexual dysfunction was evaluated via the Female Sexual Function Index (FSFI) questionnaire. Twenty-three women completed the study (12 and 11 in the fluoxetine and citalopram groups, respectively). After 1 month, the FSFI scores were 22.8 ± 7.8 and 22.5 ± 4.8 in the fluoxetine and citalopram groups, respectively. The oxytocin levels were 187.8 ± 38.8 pg/mL and 214.6 ± 23.1 pg/mL in the fluoxetine and citalopram groups, respectively. Statistical analysis did not reveal any difference in the FSFI score between the two groups after 1 month (p = 0.89). However, the oxytocin levels were significantly lower in the fluoxetine group than in the citalopram group (p = 0.05). We also observed a positive relationship between the FSFI score and oxytocin level at 1 month after starting fluoxetine or citalopram (r = 0.43, p = 0.04).A positive relationship between the oxytocin level and FSFI score supports the hypothesis that the oxytocin level plays a role in sexual dysfunction induced by SSRIs.

The most common malignant neoplasm of the head and neck region is laryngeal cancer which presents a significant international health problem. The present study aims to screen potential proteins related to laryngeal cancer by network analysis to further understanding disease pathogenesis and biomarker discovery. Differentially expressed proteins were extracted from literatures of laryngeal cancer that compare proteome profiling of patient›s tissue with healthy controls. The PPI network analyzed for up and down regulated proteins with Cytoscape Version 3.4. After PPI construction, topological properties of the two networks have been analyzed. Besides, by using MCODE. the Gene Ontology (GO) analysis, the related modules and pathways were examined. Our study screened 275 differentially changed proteins, including 136 up- and 139 down-regulated proteins. For each network, it has been considered 20 key proteins as hub and 20 as bottleneck. A number of 26 hub-bottleneck nodes is introduced for the two networks. A total of 11 modules including 6 downregulated and 5 upregulated network modules were obtained. The most significant GO function in the significant upregulated module was the RNA processing, and the most significant one in the downregulated module with highest score was the respiratory electron transport chain. Among 275 investigated proteins, 12 crucial proteins are determined that 4 of them can be introduce as a possible biomarker panel including YWHAZ, PPP2R1A, HSP90AA1, and CALM3 for human laryngeal cancer.