Iranian Journal of Pharmaceutical Research
Volume:19 Issue: 4, Autumn 2020

The process of matrix clean-up and extraction of analytes has a significant influence on the detection and determination of the analyte, especially in trace amounts. Molecularly imprinted polymers (MIPs) are solid particles that can absorb specific molecules regarding the template molecule used in the synthesis process of each type of MIP. As a result, they can be used in more effective and more specific solid-phase extraction processes. On the others hand, mycotoxins are second metabolites of molds and fungus which are potentially cytotoxic and/or genotoxic even in trace amounts, and due to extensive consumption of cereals and the great concern of public health, several methods were developed and currently are in the process of development to detect and determine the presence and the amounts of mycotoxins in cereals. This review is aimed to investigate the application and efficacy of MIPs in detecting and determination of mycotoxins in cereals.

With a facile solvothermal technique, Ssynthesis and application of Fe3O4@PPy–CuIIcomposite microspheres in the carbon ionic liquid matrix have been reported as highly sensitive sensors for voltammetric determination of Carbamazepine (CBZ). The morphology, crystal phase and structure of synthesized The nanocomposite structure was confirmed by routine methods such as transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), Fourier translation infrared spectroscopy (FT-IR), thermal gravimetric analysis (TGA), and inductively coupled plasma atomic emission spectroscopy (ICP-AES). Under the optimized conditions, differential pulse voltammetric (DPV) peak current was proportional to the CBZ concentration in the range of 0.05 to 25 μM with the detection limit (S/N=3) of 32 nM. The storage stability of the modified electrode was also investigated which showes that the current responses remain about 95.2% of their initial values, indicating the appreciable storage stability of this sensor. The proposed electrode displayed excellent repeatability and long-term stability and it was satisfactorily used for determination of CBZ in real samples (urine, and serum samples) with high recovery.

Resistance to antibiotics is a worldwide concern and community pharmacies can play a strategic role in controlling this issue through rationalizing antibiotic consumption. Considering that dispensing any type of antibiotics without a prescription is prohibited in according to Iran’s regulations, this study was conducted to quantify the rate of antibiotic dispensing without a prescription by pharmacists in Tehran, Iran. A descriptive cross-sectional study was conducted from September 2016 through May 2017. Two scenarios of common infectious symptoms including sore throat and dysuria were simulated by pharmacy student in three different regions of Tehran. Each scenario was performed in three levels of demand including requesting for any medicine, asking for a stronger medicine and direct request for an antibiotic. A total of 388 pharmacy visits were acceptable including 195 and 193 pharmacies for dysuria and sore throat, respectively. Antibiotics were provided in 39.9% of dysuria (67.5% in the first level of demand) and in 52.3% of sore throat (49% in the first level of demand) simulations. The time devoted by the pharmacists to each case was less than 60 second in more than 90% of the cases. The completion of the course of antibiotic therapy was emphasized by pharmacists in only 18% of cases in both scenarios. Our findings revealed that antibiotic dispensing without a prescription is a routine practice in community pharmacies in Tehran, Iran. Unfortunately, patient assessment and evaluation of the symptoms are not performed properly by pharmacists as well.

Aflatoxin M1 (AFM1) is a category of poisonous compounds found in milk and dairy products. The target of our research is to determine incidence and risk assessment AFM1 through the consumption of cheese in Hamadan province of Iran. Seventy cheese samples including cream cheese (n = 30) and Iranian white cheese (n = 40) were collected from different regions of Hamadan province, Iran and tested for AFM1 by ELISA technique. The estimated daily intake (EDI) and hazard index (HI) of AFM1 was determined. AFM1 was detected in 67 (95.7%) samples, including of 39 (97.5%) Iranian white cheese (mean: 115.16 ng/kg; range:

Four prenylated flavonoids including isosophoranone, sophoraflavanone G, alopecurone J, alopecurone P and a resveratrol derivative HPD (2-(4-hydroxyphenyl)-2,3-dihydrobenzo[b] furan-3,4,6-triol), were isolated from the roots of Sophora pachycarpa. The cytotoxic activity of obtained compounds was evaluated against A2780, A549, HeLa, and HCT116 human cancer cell lines. We also evaluated their histone deacetylase (HDAC) inhibitory activities. Of all compounds tested, alopecurone J was the most active with IC50 values in the range of 9.97−30.91 μM against four cancer cell lines with potent pan-HDAC inhibitory activity (IC50=0.08−3.85 μM). Molecular docking experiments of these compounds with HDAC8 displayed potential selective HDAC inhibitory. Molecular docking data showed consistent results to the in vitro experiments with the high selectivity towards HDAC8. Resveratrol group plays an important role in HDAC inhibition.

Total phenolic content (TPC) and antioxidant capacity of five different extracts (petroleum ether (40-60), dichloromethane, ethyl acetate, ethanol and ethanol-water (1:1 v/v)) of Artemisia turanica (A. turanica) aerial parts were determined and phytochemical study on the most promising extract was carried out. Folin–Ciocalteu method, 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging test, β-carotene bleaching (BCB) method and ferrous ion chelating (FIC) assay were performed. Vacuum liquid chromatography (VLC) and semi-preparative HPLC were used for bioassay-guided phytochemical isolation. Structures of isolated compounds were established using spectroscopic analysis including NMR and MS. Among all the extracts analyzed, the hydroethanolic extract exhibited the highest phenolic content and antioxidant activity. VLC of this extract yielded seven fractions (A to G) which were subjected to all antecedent experiments. The same sample (Fraction D) showed the highest total phenolic content and free radical scavenging activity but the only statistically significant correlation between TPC and EC50 values was observed for BCB.3,5-dicaffeoylquinic acid (isochlorogenic acid A), and 4,5-dicaffeoylquinic acid (isochlorogenic acid C) were isolated from the most active fraction. Antioxidant activity of A. turanica is probably partly due to the presence of isomers of isochlorogenic acid.

Prevention and treatment of neuropathic pain (NP) is one of the most difficult problemsin clinical practice since the underlying mechanism of NP is unclear. In previous studies, theincreased production of nitric oxide (NO) has been closely linked to the induced NP. In thisstudy, we assessed the effect of atorvastatin through NO mechanism, on inflammation, thermalhyperalgesia, thermal allodynia, and mechanical allodynia as well as sciatic nerve histologicalscore in rat with chronic constriction injury (CCI) model. Finally, we specified the role ofcytokines such as TNF-α and IL-6 in the spinal cord. Treatment with atorvastatin and L-NAME(NO inhibitor) attenuated the thermal hyperalgesia, thermal allodynia and mechanical allodyniainduced by CCI. The antinociceptive consequence was better elevated with a combination ofatorvastatin and L-NAME in comparison with the other groups. In addition, the treatment withthese drugs also attenuated the CCI-induced TNF-α and IL-6 level in the spinal cord. Furthermore,the histological analysis showed a low level of inflammation in the sciatic nerve in the CCI rats cotreatedwith atorvastatin and L-NAME. Findings of our study in NP-induced CCI in the rat modeldemonstrate that inhibition of NO displays antinociceptive and anti-neuroinflammatory effectsof atorvastatin in peripheral and central nervous system. In addition, we found that inhibitionof the NO by atorvastatin could be one of the most important anti-inflammatory pathways ofatorvastatin effect.

99mTc-HMPAO labeled platelet (LP) imaging may integrate thrombosis imaging into routine clinical procedures. In the current study, we assessed the feasibility of the use of 99mTc-HMPAO LP for imaging of small clots in an animal model. Thrombosis was induced by application of FeCl3 solution in the distal part of the inferior vena cava (IVC) of a 6100 g anesthetized rabbit and in a male Wistar rat weighing 420 g. Twenty minutes later, 178 MBq 99mTc-HMPAO LP was injected. 99mTc-HMPAO LP preparation was done as defined and standardized in a previous report. Whole body and SPECT imaging were done 60, 90, and 120 min after tracer injection. Then, the clotted part of the vein was extracted and then its activity and pathologic evaluations were compared with the proximal part of the IVC at a similar volume.A 17 × 6 mm clot was clearly detected with both planar and SPECT imaging. The count to pixel ratio (CPR) of the clotted part of the vein was 35, 40, and 40 compared to the non-clotted vein (i.e. 19, 18, and 21) at 60, 90, and 120 min, respectively. After clot extraction, the CPR decreased to 14. The clot activity was 0.44 MBq compared to 0.01 MBq of the normal control vein. Also, clot induction was pathologically proven.99mTc-HMPAO LP preparation is logistically possible in clinical nuclear medicine and the ability of imaging small size clots encourages future trials for real clinical thrombotic scenarios.

Further investigations on phytochemical constituents of dichloromethane extract fromroots of Salvia lachnocalyx (S. lachnocalyx) led to the isolation and identification of eightknown diterpenoids from this plant for the first time. The chemical structures of the purifiedcompounds were elucidated using spectroscopic analyses including EI-MS, 1H and 13C NMR andby comparison of the resulting spectra with those reported in the literature. Then, the cytotoxicactivity of identified compounds was examined against two human cancer cell lines MCF-7(human breast adenocarcinoma) and K562 (human chronic myelogenous leukemia). Moleculardocking of promising cytotoxic compounds were performed by AutoDock Tools 1.5.4 programin the active site of Topoisomerase I. Eight known diterpenoids; 12-hydroxysapriparaquinone(1), 15-deoxyfuerstione (2), horminon (3), 7α-acetoxyroyleanone (4), 11β-hydroxymanoyloxide (5), microstegiol (6), 1-keto-aethiopinone (7) and 14-deoxycoleon U (8) were isolated ofdichloromethane extract from roots of salvia lachnocalyx. Compounds 2, 3, 6, and 8 showedcytotoxic activity against MCF-7 (human breast adenocarcinoma) and K562 (human chronicmyelogenous leukemia) cell lines with IC50 values in the range of 2.63-11.83 μg/mL. The inhibitionof” topoisomerase I” was suggested by molecular docking calculations as the mechanism ofcytotoxicity of the tested compounds. According to cytotoxic assay and docking results, it issuggested that compounds 2, 3, 6, and 8 have good potential as anticancer agents.

Diabetes mellitus is a chronic disease characterized by hyperglycemia mainly because of the absolute or relative deficiency of insulin hormone. The dipeptidyl peptidase-IV inhibitors represent a class of glucose-lowering agents potentiating the action of the incretin hormones glucagon-likepeptide-1 and glucose dependent insulinotropic polypeptide, which are secreted from the intestinal endocrine cells in response to food ingestion to stimulate insulin secretion from pancreatic beta cells. Natural products have traditionally been used for curing many diseases. In this study, in vitro biological evaluation of the isolated compounds calotoxin, calotropin, pectolinarigenin, apigenin7-O-(3",6"-di-O-E-p-coumaroyl)-β-glycoside and extracts of Calotropis procera, Ephedra foeminea, Artemisia herba-alba, Hylocereus undatus and Marrubium vulgare showed potential inhibitory activity, where the butanol extract of Calotropis procera was found to have 85.3% inhibition of dipeptidyl peptidase-IV at 0.2 mg/100 µL concentration.

The endocannabinoid system plays an important neuromodulatory role in the periphery and central nervous system, which can regulate several physiological processes. The inhibition of enzymatic activities responsible for hydrolysis anandamide and other endogenous fatty acid amides, enhances cannabinoid receptors activity indirectly that may prove to be useful drugs for the treatment of range of ailments including pain, anxiety, and other central nervous system disorders. In this study, we designed, synthesized, and evaluated novel fatty acid amide hydrolase (FAAH) inhibitors based on 4-aminobenzohydrazide derivatives. Most of the synthesized compounds exhibited a proper affinity for the catalytic triad of FAAH in docking studies and had a considerable in-vitro FAAH inhibitory activity in comparison with JZL-195, a potent inhibitor of FAAH. Compound 2-(2-(4-(2-carboxybenzamido)benzoyl)hydrazine-1-carbonyl)benzoic acid, 12, was found to be the most potent inhibitor with IC50 value of 1.62 nM targeting FAAH enzyme.

Proton pump inhibitors (PPIs) are recommended as first line treatments for gastroesophageal reflux disease (GERD). Failure to PPIs has been mentioned as a problem in pharmacotherapy of GERD. The present study compared the symptom relief, quality of life (QoL) and adverse drug reactions (ADRs) of omeprazole plus buccal buspirone with that of omeprazole alone.This was a prospective, randomized trial between buccal buspirone (10 mg/d) plus omeprazole (20 mg/d) and omeprazole (20 mg/d) plus placebo administered for 4 weeks to patients with GERD symptoms. Patients who had GERD symptoms enrolled in this study.67 patients were randomly assigned to either the buspirone plus omeprazole group (n = 33) or the placebo plus omeprazole group (n=34). Finally, 58 patients completed the study (29 in each group). Treatment response rates in each drug group were evaluated according to the Frequency Scale for the Symptoms of GERD (FFSG). The QoL and ADRs have been also evaluated too.The treatment score rates for symptom relief according to the FFSG were 7.13 ± 5.13 in the buspirone group and15.34 ±8.17in the placebo group. Regarding FFSG score, there is a significant difference between the groups (p < 0.0001). QoL were 6.86 ± 6.65 and 27.2 ± 20.95 in placebo and buspirone group respectively after four weeks and there is a significant difference in two groups (p < 0.0001).The total incidence of ADRs were similar in the buspirone and placebo groups (p = 0.36). A combination of buccal buspirone plus omeprazole may be a more effective treatment for GERD than omeprazole alone.

Type 1 diabetes (T1D) occurs as a consequence of an autoimmune attack against pancreatic-β cells. Due to a lack of a clear understanding of the T1D pathogenesis, the identification of effective therapies for T1D is the active area in the research. The study purpose was to prioritize potential drugs and targets in T1D via systems biology approach. Gene expression data of peripheral blood mononuclear cells (PBMCs) and pancreatic-β cells in T1D were analyzed and differential expressed genes were integrated with protein-protein interactions (PPI) data. Multiple topological centrality parameters of extracted query-query PPI (QQPPI) networks were calculated and the interaction of more central proteins with drugs was investigated. Molecular docking was performed to further predict the interactions between drugs and the binding sites of targets. Central proteins were identified by the analysis of PBMC (MYC, ERBB2, PSMA1, ABL1 and HSP90AA1) and pancreatic β-cells QQPPI networks (HSP90AB1, ESR1, RELA, RAC1, NFKB1, NFKB2, IKBKE, ARRB2, SRC). Thirteen drugs targeted eight central proteins were identified by further analysis of drug-target interactions. Some drugs which investigated for diabetes treatment in the experimental models of T1D were prioritized by literature verification, including melatonin, resveratrol, lapatinib, geldanamycin, eugenol and fostaminib. Finally, according on molecular docking analysis, lapatinib-ERBB2 and eugenol-ESR1 exhibited highest and lowest binding energy, respectively. This study presented promising results for the prioritization of potential drug-targets which might facilitate T1D targeted therapy and its drug discovery process more effectively.

Cardiovascular diseases (CVD) have become increasingly life-threatening during recent decades. Several studies have shown that matrix metalloproteinase-9 (MMP-9) plays an important role in the process of atherosclerosis and heart remodeling. On the other hand, Vitamin D deficiency has been recognized as a risk factor for CVD. According to the prevalence of vitamin D deficiency in our country, Iran, we aimed to evaluate the relationship between vitamin D status and the level of MMP-9 in patients undergoing percutaneous coronary intervention (PCI). In this prospective cross-sectional study, patients who were candidates for elective coronary angioplasty were included. Baseline serum MMP-9 and vitamin D levels were measured before intervention. Patients were categorized into three groups: Vitamin D-severely deficient (≤ 10 ng/ml), vitamin D-moderately deficient (11-20 ng/ml), and vitamin D-insufficient/sufficient (> 21 ng/ml). Totally, 150 patients were assessed. The analysis showed that serum MMP-9 levels were higher in patients with lower vitamin-D concentrations. A significant inverse correlation was found between MMP-9 concentration and 25(OH) vitamin D level (P = 0.039). According to our results, it may be concluded that low levels of vitamin D may lead to more vulnerable atherosclerotic plaques and consequently more cardiovascular adverse effects in post-PCI patients.

A sensitive method using ion-pair extraction was developed by liquid chromatography tandem mass spectrometry (LC–MS/MS) for measurement of 4-methylimidazole (4-MI) in NMRI mice plasma and cerebrospinal fluid (CSF). Detection was done by electrospray positive ionization mass spectrometry in the multiple-reaction monitoring (MRM) mode. The validation method was applied to quantification of 4-MI in plasma and CSF samples using oral doses of 100, 200, and 300 mg/kg in NMRI mice. The efficiency of the method was evaluated in terms of linearity (R2> 0.99), recovery (98–107%, 3 levels) and precision (8–10%, 3 levels, n = 6). Limit of detection (LOD) and limit of quantification (LOQ) were 25 ng/ml and 50 ng/mL, respectively. The results obtained showed that the exposure to oral doses of 4-MI in mice makes different concentrations in plasma and CSF and causes significant changes in mice. This study was the first report for determination of 4-MI in plasma and CSF samples in mice. Our results suggest that LC-MS/MS-based on ion-pair extraction is a robust method with high detection ability for measurement of 4-MI in plasma and CSF samples. Therefore the developed method can be useful for evaluation and monitoring of imidazole derivatives in biological samples.

Stem cell therapy is noted for its clinical effect in the treatment of neuropathic pain. The aim of this study was to investigate the potential anti-apoptotic and anti-inflammatory effects of adipose-derived mesenchymal stem cells (AD-MSCs) and fibroblast growth factor 1 gene-transfected adipose-derived mesenchymal stem cells (AD-MSCs FGF1) on chronic constriction injury (CCI) of the rat’s sciatic nerve.

Rats underwent CCI, were treated with AD-MSCs and AD-MSCs FGF1. The involvement of Bax, Bcl2 and caspases 3, the major contributors of apoptosis, and the markers of inflammatory including Iba-1, IL1-β and MMP-2 were evaluated in the lumbar portion (L4-L6) of the spinal cord through western bloating at days 3 and 14.

The ratio of Bax/ Bcl2, cleaved caspases 3, MMP-2, IL-1β, and Iba1 was elevated on day 14, in CCI animals as compared to sham-operated animals and decreased following treatment with both AD-MSCs and AD-MSCs FGF1. However, the effect of AD-MSCs FGF1 was significantly higher than AD-MSCs.

These data suggest that the administration of AD-MSCs FGF1 through modulating apoptosis and neuroinflammation could be considered as a promising medicine for the treatment of neuropathic pain.

Oxidative stress (OS) is a common biological event in polycystic ovarian syndrome (PCOS), causing oocytes to undergo OS-induced changes. Sirtuin3 (Sirt3) has a critical role in oocyte maturation through the modulation of OS. In the current study, we compared the effects of metformin and clomiphene citrate on the expression of the Sirt3 gene in oocytes obtained from mice induced by PCOS. The induction of PCOS was performed by the single injection of estradiol valerate. Animals were divided into control, PCOS, metformin (500 mg/kg), and clomiphene (18 mg/kg) groups. At the end of the experiment, the levels of LH and FSH were determined using the ELISA method. Ovarian tissues were evaluated histologically, and the expression of the Sirt3 gene was analyzed by the Real-time PCR. The induction of PCOS led to an increase in the ratio of LH/FSH elevation, the number of follicle atresia, as well as the presence of hydrated cysts. The results showed that both treatment regimens returned the altered parameters to the baseline values. The gene of Sirt3 was significantly (p< 0.001) reduced in the PCOS group in compare to control. Also, no significant difference was found in the expression of Sirt3 between clomiphene and PCOS group, whereas, in the metformin group, Sirt3 expression had the higher rate of expression in comparison with the PCOS group (p< 0.05). The administration of metformin and clomiphene showed that metformin is capable of preventing the downregulation of the Sirt3 gene in oocytes collected from PCOS mice.

Several formulations of herbal plants have been extensively applied to treat diseases. Satureja khuzistanica (S. khuzistanica) is an Iranian traditional plant with a wide range of benefit effects on different diseases. In this study, we aimed to prepare silver nanoparticles from S. khuzistanica via the green synthesis method and investigate the anti-cancer effects on the HT29 cell line. To synthesize Ag-S. Khuzistanica, 50 ml S. khuzistanica extract and 1 mM AgNO3 were mixed and shaken at room temperature for 72 h. To determine the Ag-S. Khuzistanica nanoparticle characterization, XRD, FTIR, and TEM methods were done. In addition, MTT assay and real time PCR and annexin V/PI staining were performed to investigate the cytotoxicity, bcl-2 and bax gene expression and percentage of apoptotic cells. Our findings showed that Ag-S. khuzistanica is a spherical crystalline nanoparticle with the size less than 100 nm. MTT analysis showed that 375, 750, 1500 and 3000 µg/ml Ag- S. Khuzistanica significantly decreased the cell viability of HT29 cells. Ag -S. khuzistanica significantly reduced bcl-2 and increased apoptotic index expression at 375, 750, 1500, 3000 µg/ml Ag- S. Khuzistanica in a dose-dependent manner. Furthermore, cell staining with Annexin V/PI showed that treating Ag- S. Khuzistanica led to increasing in apoptotic cells. In conclusion, the formulation of Ag -S. khuzistanica has the apoptotic properties on the colorectal cancer cell line.

Epileptic seizure is phenomenon of abnormal synchronous neuronal discharge of a set of neurons in brain as a result of neuronal excitation. Evidence shows the nitric oxide (NO) involvement in neuronal excitability. Moreover, the role of NO-mediated cyclic guanosine monophosphate (cGMP) activation in seizure pathogenesis is well-established. Sumatriptan is a selective agonist of 5-Hydroxytryptamine1B/D auto-receptor, has been reassessed for its neuroprotection. This study was aimed to explore the anticonvulsant effect of sumatriptan through possible involvement of NO-cGMP pathway in mice. For this purpose, the protective effect of sumatriptan on PTZ-induced clonic seizure threshold (CST) was measured using NO-cGMP pathway inhibitors including N(G)-nitro-L-arginine (L-NNA, 1, 5, and 10 mg/kg), 7-nitroindazole (7-NI, 30, 45, and 60 mg/kg), aminoguanidine (AG, 30, 50, and 100 mg/kg), methylene blue (MB, 0.1, 0.5, and 1 mg/kg) and sildenafil (5, 10, and 20 mg/kg). The involvement of nitrergic system was further confirmed by measurement of nitrite levels by Griess reaction. The gene expression of neuronal nitric oxide synthase (nNOS) and subunits of soluble guanylyl cyclase (sGC) was studied using qRT-PCR analysis. Acute administration of sumatriptan (1.2 and 0.3 mg/kg) in combination with subeffective doses of NOS, sGC, and phosphodiesterase 5 inhibitors significantly reversed the PTZ-induced CST (P≤0.001). The nitrite level in prefrontal cortex was significantly attenuated by sumatriptan (P≤0.01). Furthermore, sumatriptan downregulated the PTZ-induced mRNA expression of nNOS, and α1, α2, and β1 genes in cerebral cortex of mice (P≤0.0001). In conclusion, the anticonvulsant activity of sumatriptan at least, in part, is mediated through inhibiting NO-cGMP pathway.

Tumorigenesis must be understood as a summary of altered genetic and genomic changesresulting in the inactivation of tumor suppressor genes (TSGs). One of the characterizations ofepigenetic alterations is DNA methylation. Epigenetic alteration of the p16INK4a, p14ARF,p15INK4b, and DNA methyltransferase 1 gene (DNMT1) expression occurs in hepatocellularcarcinoma (HCC) and pancreatic cancer frequently. DNA methyltransferase inhibitors (DNMTIs),such as zebularine, play a signifcant effect on the demethylation and reactivation of TSGs. Thisstudy aimed to investigate the effect of zebularine on p16INK4a, p14ARF, p15INK4b, and DNAmethyltransferase 1 gene expression, cell growth inhibition, and apoptosis induction in HCCPLC/PRF5 and pancreatic cancer PA-TU-8902 cell lines. Both cell lines were cultured and treatedwith zebularine at different times. The MTT assay, real-time quantitative reverse-transcriptionpolymerase chain reaction (qRT-PCR), and flow cytometry were used to determine cell viability,gene expression, and apoptotic cells, respectively. The result indicated that zebularine inhibitedcell growth of both cell lines signifcantly as time- and dose-dependent manner (P < 0.007). Theagent induced signifcant down-regulation of DNMT1 and up-regulation of p16INK4a, p14ARF,p15INK4b (P < 0.028). Besides, it had a signifcant apoptosis effect on both cell lines (P < 0.001).This compound had a strong signifcant effect on PLC/PRF5 in comparison to PA-TU-8902 cells.Concluding, zebularine inhibited PLC/PRF5 and PA-TU-8902 cell growth and induced apoptosisin these cell lines. The most likely mechanism underlying the zebularine played its role involvesdown-regulation of DNMT1 and up-regulation of p16INK4a, p14ARF, and p15INK4b genes.

Retinoblastoma (RB) is a common malignancy in childhood, with an incidence of 1 per20,000 live births. Several approaches such as chemotherapy, laser, and radiotherapy have beenused for the treatment of RB. However, the effectiveness of these methods is not suffcient and themechanisms involved in the pathogenesis of the disease are not well understood. The disruptionof the apoptotic process is considered as one of the mechanisms involved in the pathogenesisof RB. This study was designed to examine the in-vitro selective toxicity of cold atmosphericplasma (CAP) on RB cells’ mitochondria and lysosomes. The results showed that CAP decreasedcell viability and GSH content and also increased caspase-3 activity and lipid peroxidation(LPO) in cancerous ocular cells isolated from the rat model of RB compared to the normal ratocular cells. Furthermore, results demonstrated that CAP signifcantly increased ROS generation,mitochondrial membrane potential (MMP) collapse, mitochondrial swelling, and cytochrome crelease only in cancerous rat ocular mitochondria but not the normal rat ocular mitochondria.Furthermore, our results demonstrated that CAP signifcantly increased the lysosomal damageonly in the cancer group. Altogether, the results of the study showed that CAP could selectivelyinduce apoptosis on RB mitochondria. CAP may therefore be considered as a promising candidatefor further in-vivo and clinical researches to reach a new anti- RB drug.

Apricot (Prunus armeniaca L.) is a fruit cultivated in various parts of the world. Both sweet and bitter kernels of apricot have been used for the treatment of different diseases such as loss of memory in Iranian traditional medicine (ITM). In the present study, the inhibitory activity of sweet and bitter extracts of apricot kernels towards cholinesterase (ChE) enzymes, both acetyl and butyrylcholinesterase was examined through Ellman’s method. In addition, neuroprotectivity of aqueous extracts and amygdalin were investigated against H2O2-induced cell death in PC12 neurons. Among them, the best acetylcholinesterase (AChE) inhibitory activity (IC50 = 134.93 ± 2.88 µg/mL) and neuroprotectivity (P-value < 0.0001) were obtained by the aqueous extract of bitter type. It was found that all extracts showed no butyrylcholinesterase (BChE) inhibitory activity.

In this study, we evaluated the effects of nanofiber and film polymers with doxycycline for treating a wound in a diabetic rat model. 108 male rats were divided into six groups, the control group, the diabetic control, and the groups were diabetic rats receiving different wound dressing. At the 3rd, 7th, and 14th days, macroscopic/histologic imaging and tissue sampling were performed. Tissues were analyzed for IL-1β, TNF-α, IL-10, TIMP-1, and MMP-2 by using ELISA. Dressings of chitosan, polyvinyl alcohol and doxycycline increased the rate of wound closure, the volume of collagen, dermal, and epidermis; in addition, it increased the number of fibroblasts and basal cell epidermis cells, vascular length, and decreased the number of neutrophil cells. Inflammatory cytokines and MMP-2 were decreased, and anti-inflammatory IL-10 and TIMP-1 were increased. It was ultimately attained that the combination of chitosan/ polyvinyl alcohol /doxycycline could be a useful dressing for the healing of diabetic wounds.

The present study introduces a novel method for encapsulation of the acid-labile drug calledOmeprazole using Lactobacillus acidophilus (L. acidophilus) ATCC 4356 S-layer protein. Beforepreparing the Omeprazole suspension, a series of preliminary studies were performed on theOmeprazole powder. For this purpose, some parameters such as melting point, IR spectrum,UV spectrum, and the particle size of Omeprazole powder were investigated. The size reductionprocess was done in order to achieve an ideal formulation. Ultimately, the resulting powder hadan average particle size of 35.516 μm and it was almost uniform. After calculating the amountof S-layer protein required for complete covering of drug particles, the effect of different factorson the drug coating process was investigated with one factor at a time method. Then stability ofcoated Omeprazole was evaluated in acetate buffer (pH 5). Finally, the maximum coat of drugparticles was determined using S- layer protein of Lactobacillus acidophilus ATCC 4356 at 25 °Cfor 2 h, shaking rate of 100 rpm and ratio of 2:1 for S-layer protein amount/Omeprazole Surfacein Tris hydrochloride buffer medium (50 mM, pH 8). The coating of Omeprazole by the S-layerprotein decreased the drug decomposition rate up to 2.223.

Septic shock, known as the most severe complication of sepsis, is a serious medical condition that can lead to death. Clinical symptoms of sepsis include changes in body temperature in the form of hypothermia or hyperthermia, tachypnea or hyperventilation, tachycardia, leukocytosis or leukopenia, and variations in blood pressure, as well as altered state of consciousness. One of the main problems in septic shock is poor response along with reduced vascular reactivity to vasopressors used to increase blood pressure. In addition to being the state-of-the-art treatment including volume load and vasopressor, use of alpha-2 agonists e.g. dexmedetomidine (DXM) in septic shock can reduce vasopressors needed to restore adequate blood pressure. They can further moderate massive release of endogenous catecholamine. Therefore, the purpose of this study was to investigate the effect of DXM on outcomes of patients with septic shock, especially their needs for vasopressors and impacts on their hemodynamic status. This single-blind randomized controlled trial was performed on a total number of 66 patients with septic shock admitted to the intensive care unit (ICU) of Imam Khomeini Teaching Hospital in the city of Sari, in northern Iran. To this end, DXM (0.6 µg/kg/h) and normal saline (6ml/kg/h) were infused for 12 h in the study and control groups, respectively. The results revealed that DXM could increase mean arterial pressure (MAP) (p=0.021), systolic blood pressure (SBP) (p=0.002), and diastolic blood pressure (DBP) (p=0.32) accompanied by reduced heart rate (p

As stated in many ethnobotany studies, Potentilla genus is traditionally used in the treatment of wound healing. In this study, we aimed to investigate to time-course effects of the methanolic extract of Potentilla erecta (P. erecta) (MEPE) on diabetic wounds. The subject of the experiments was 36 Wistar rats, divided into three main groups: non-diabetic control (NDM), diabetic control (STZ-DM), and P. erecta-treated (MEPE). Diabetes was induced by streptozotocin (STZ). Full-thickness excisional skin wounds were opened in rats. The wounds were treated with P. erecta root extract in the MEPE groups. The wound area, wound contraction rate, collagen, thiobarbituric-acid reactive substances (TBARs), nitric oxide (NOx), and glutathione (GSH) levels in wound tissue were determined for the evaluation of the wound healing on days 0, 3 and 7. Phenolic compounds of MEPE were determined by RP-HPLC-UV. The antioxidant properties were spectrophotometrically determined and the antibacterial properties were tested using the microwell-dilution method. Our results demonstrated that MEPE signifcantly increased wound contraction rate compared to the STZ-DM group on days 3 and 7. MEPE treated rats showed a statistical increase in the levels of NOx, GSH, collagen and a statistical decrease in the levels of TBARs. Our results, for the frst time, may indicate that P. erecta root extract improves and accelerates diabetic wound healing and also alters oxidative events.

Idiopathic Thrombocytopenic Purpura (ITP) is a multifactorial disease with decreased count of platelet that can lead to bruising and bleeding manifestations. This study was intended to identify critical genes associated with chronic ITP. The gene expression profile GSE46922 was downloaded from the Gene Expression Omnibus database to recognize Differentially Expressed Genes (DEGs) by R software. Gene ontology and pathway analyses were performed by DAVID. The biological network was constructed by Cytoscape. Molecular Complex Detection (MCODE) was applied for detecting module analysis. Transcription factors were identified by the PANTHER classification system database and the gene regulatory network was constructed by Cytoscape. 132 DEGs were screened from comparison newly diagnosed ITP than chronic ITP. Biological process analysis revealed that the DEGs were enriched in terms of positive regulation of autophagy and prohibiting apoptosis in the chronic phase. KEGG pathway analysis showed that the DEGs were enriched in the ErbB signaling pathway, mRNA surveillance pathway, Estrogen signaling pathway, and Notch signaling pathway. Additionally, the biological network was established, and five modules were extracted from the network. ARRB1, VIM, SF1, BUB3, GRK5, RHOG were detected as hub genes that also belonged to the modules. SF1 also was identified as a hub-TF gene. To sum up, microarray data analysis could perform a panel of genes that provides new clues for diagnosing chronic ITP.

Screening of bioactive compounds with potential binding affinity to DNA as one of the target molecules in fighting against cancer cells has gained the attention of many scientists. Finding such compounds in the cellular content of microorganisms, especially marine bacteria as valuable and rich natural resources, is of great importance. Microbacterium sp. RP581, as a member of Actinobacteria phylum, was isolated from the Persian Gulf coastal area and the production of the target compound was optimized using statistical methods in cheap culture ingredients. The purification of the target compound was performed by flash chromatography and preparative HPLC. Both molecular and structural analyses indicated that the compound was an indole derivate which was tentatively named as Microindoline 581. Interaction of Microindoline 581 with genomic and circular DNA revealed that this compound can cause double- strand breaks through binding to the DNA. The analysis of cellular growth and proliferation of various cancer cell lines suggested proper and specific effect Microindoline 581 towards HepG2 cells with an IC50 of 172.2 ± 1.7 µM. Additional studies on cell migration inhibition and cell-death induction indicated a concentration-dependent inhibitory effect on proliferation and induction of death of HepG2 cells. The selective action of Microindoline 581 which was isolated from the Microbacterium sp. RP581 in killing HepG2 cells might be due to its specific metabolism in those cells as a precursor.

Biogenic synthesis of silver nanoparticles (SNPs) have great attention of scientists, as it provide clean, biocompatible, non-toxic and inexpensive fabrication. In this study, Feijoa sellowiana leaf extract was used for synthesizing SNPs which reduces silver nitrate into silver zero-valent. SNPs were characterized by UV, FTIR, XRD, SEM-EDS and TEM analysis. They were also examined for their biological activities. The presence of biosynthesized SNPs was characterized by UV–visible spectroscopy and also crystal nature of SNPs identified with XRD analysis. FT-IR spectrum was used to confirm the presence of different functional groups in the biomolecules which act as a capping agent for the nanoparticles. The morphology of SNPs was explored using SEM and the presence of silver was confirmed by elemental analysis. The size of the nanoparticles was in the range of 20–50 nm determined by TEM. The green synthesized SNPs showed a good antibacterial activities against both gram-negative and gram-positive bacteria and also in resistant clinical isolated pathogens. Furthermore, the green synthesized SNPs showed reliable anticancer activity on the gastric adenocarcinoma (AGS) and breast (MCF-7) cancer cell lines with little effect on normal (HFF) cells. The in vitro antioxidant activity of SNPs showed a significant effect on scavenging of free radicals and iron chelating activity.

The present study was designed to primarily examine the therapeutic potential of the herbal extract of Melilotus Offcinalis for the treatment of multiple sclerosis in the experimental autoimmune encephalomyelitis (EAE) model of the disease. The animal model was induced in C57BL/6 female mice, and then the herbal extract was intraperitoneally administered for a total of 21 days after the frst day of post-immunization. The phenotypic signs, a gene expression profle of inflammatory cytokines, antioxidant state, and pathological hallmarks of the disease in the corpus callosum were evaluated. The prophylactic administration of Melilotus Offcinalis attenuates the clinical signs of the disease. It signifcantly declined the gene expression of proinflammatory cytokines like IL-6, TNF-α, and IFN-γ. This herbal extract also surged the gene expression, as an anti-inflammatory cytokine. The gene expression of Glutathione peroxidase and Catalase (antioxidant enzymes) was meaningfully higher in the treatment group. Pathological evaluation of corpus callosum cross-sections by Luxol Fast Blue staining revealed preserved myelin sheath in the treated group compared to the EAE mice. The results of our assay confrmed that immunomodulatory and antioxidant features of the herbal extract of Melilotus Offcinalis ameliorated the EAE  severity. This study fnding disclosed the therapeutic effciency of this compound in MS treatment.

The paper in hand seeks to evaluate the tumor-suppressive and apoptotic effects of L. paracasei X12 in 1, 2‐dimethylhydrazine (DMH)-induced rat colon carcinogenesis. The rats were divided into three groups (n = 8-12 per group); L. paracasei X12 was administrated to these animals for forty weeks. The fndings of this study indicated that L. paracasei X12 administration prevented severe weight loss in DMH-treated rats. It was also determined that L. paracasei X12 administration could prevent the neoplasia incidence, cell proliferation and it also could suppress the tumors’ growth. Additionally, a signifcant improvement was observed in apoptosis indexes and cell proliferation in probiotic-treated rats. In conclusion, this study provides insights into the therapeutic potential of L. paracasei X12 with emphasis on the issue that modulation of apoptosis pathway could leave benefcial effects in the prevention and suppression of colorectal cancer (CRC). However, further studies are in support to clarify the mechanisms involved in the tumor-suppressive effect of probiotics.

This study aimed to characterize and evaluate leishmanicidal and trypanocidal action as well as cytotoxicity on macrophages and antioxidant ability of extracts, obtained by supercritical CO2 and ultrasound-assisted extractions of Uvaia (Eugenia pyriformis) leaves.

Leaves from E. pyriformis were submitted to supercritical CO2 (E1) and ultrasound-assisted (E2) extractions. The characterization of extracts was done using GC-MS and HPLC. L. amazonensis (promastigotes) and T. cruzi (epimastigotes and trypomastigotes) were treated with crescent concentrations of E1 and E2. After this, parasites were counted and the percentage of inhibition and IC50/LC50 was calculated. Murine macrophages were treated with both extracts for 48 h and after that, the cellular viability was determined and CC50 was calculated. DPPH method was used to determine the antioxidant capacity of both extracts.

The results of identification showed a great amount of α and β-amyrin in E1 and E2. Both extracts showed growth inhibition of L. amazonensis with an IC50 of 5.98 and 9.38 μg/mL to E1 and E2, showing a selectivity index > 30. In trypanocidal tests, an LC50 of 16.69 and 7.80 μg/mL (trypomastigotes) and IC50 of 5.56 and 34.34 μg/mL (epimastigotes) was reached by E1 and E2. Both extracts showed no toxicity to macrophages and an antioxidant capacity similar to the positive control (tocopherol).

This is the first study demonstrating the activity of an amyrin rich-extract against microorganisms that cause Chagas disease and leishmaniasis, as well as its antioxidant capacity, justifying further studies for future in-vivo tests.