Iranian Journal of Basic Medical Sciences
Volume:20 Issue: 1, Jan 2017

Ferula persica, is the well-known species of the genus Ferula in Iran and has two varieties: persica and latisecta. They have both been extensively used in traditional medicine for a wide range of ailments. A great number of chemical compounds including sesquiterpene coumarins and polysulfides have been isolated from this plant.
Fresh plant materials, crude extracts and isolated components of F. persica have shown a wide spectrum of pharmacological properties including anti-pigmentation in Serratia marcescens, cytotoxic, antibacterial, anti-fungal, anti-leishmanial, cancer chemopreventive, reversal of multi-drug resistance, anti-inflammatory and lipoxygenase inhibitory activity. The present review summarizes the data available regarding the chemical constituents and biological activities of F. persica.

This study evaluates the effect of substitution of microcrystalline cellulose (MCC) with ethylcellulose (EC) on mechanical and release characteristics of theophylline pellets.
The effect of addition of EC was investigated on characteristics of pellets with varying drug content prepared by extrusion-spheronization. Also the effect of type of granulating liquid (water or Surelease) was investigated on characteristics of selected pellets. The pellets were characterized for particle size (sieve analysis), mechanical strength, morphology (microscopy), thermal (DSC) and dissolution behaviors.
The exrtudability of the wet mass was reduced upon inclusion of EC so that complete replacement of MCC was not possible. Increase in EC percentage led to lower production yield and formation of pellets with larger diameter and slightly rough surfaces. Inclusion of EC also affected the mechanical properties of pellets but had negligible effect on drug release profile. The surface of selected pellets became smoother and their production yield increased upon the use of Surelease as granulating liquid. In addition the rate of drug release decreased to some extent when Surelease was used.
Preparation of theophylline pellets with EC alone was not possible in process of extrusion-spheronization. Partial replacement of MCC with EC changed physicomechanical properties of pellets but hardly affected drug release. Although the use of Surelease as granulation liquid slightly decreased the rate of drug release, desirable matrix pellets with sustained drug release could not be produced. Despite this outcome however, these pellets could benefit from reduced coating thickness for drug release control.

to investigate the chronopharmacological effects of growth hormone on executive function and the oxidative stress response in rats.
Fifty male Wistar rats (36-40 weeks old) had ad libitum access to water and food and were separated into four groups: diurnal control, nocturnal control, diurnal GH-treated, and nocturnal GH-treated animals. Levels of Cu, Zn superoxide dismutase (Cu,Zn-SOD), and superoxide release by spleen macrophages were evaluated. For memory testing, adaptation and walking in an open field platform was used. GH-treated animals demonstrated better performance in exploratory and spatial open-field tests.
The latency time in both GH-treated groups was significantly lower compared with the latency time of the control groups. The diurnal GH treatment did not stimulate superoxide release but increased the CuZn-SOD enzyme levels. The nocturnal GH treatment did not influence the superoxide release and CuZn-SOD concentration. GH treatment also resulted in heart atrophy and lung hypertrophy.
Growth hormone treatment improved the performance of executive functions at the cost of oxidative stress triggering, and this effect was dependent on the circadian period of hormone administration. However, GH treatment caused damaging effects such as lung hypertrophy and heart atrophy.

To study the effect of low-frequency vibration on bone marrow stromal cell differentiation and potential bone repair in vivo.
Forty New Zealand rabbits were randomly divided into five groups with eight rabbits in each group. For each group, bone defects were generated in the left humerus of four rabbits, and in the right humerus of the other four rabbits. To test differentiation, bones were isolated and demineralized, supplemented with bone marrow stromal cells, and implanted into humerus bone defects. Varying frequencies of vibration (0, 12.5, 25, 50, and 100 Hz) were applied to each group for 30 min each day for four weeks. When the bone defects integrated, they were then removed for histological examination. mRNA transcript levels of runt-related transcription factor 2, osteoprotegerin, receptor activator of nuclear factor k-B ligan, and pre-collagen type 1 a were measured.
Humeri implanted with bone marrow stromal cells displayed elevated callus levels and wider, more prevalent, and denser trabeculae following treatment at 25 and 50 Hz. The mRNA levels of runt-related transcription factor 2, osteoprotegerin, receptor activator of nuclear factor k-B ligand, and pre-collagen type 1 a were also markedly higher following 25 and 50 Hz treatment.
Low frequency (25–50 Hz) vibration in vivo can promote bone marrow stromal cell differentiation and repair bone injury.

Neurotrophins (NTs) exert various effects on neuronal system. Growing evidence indicates that NTs are involved in the pathophysiology of neuropathic pain. However, the exact role of these proteins in modulating nociceptive signaling requires being defined. Thus, the aim of this study was to evaluate the effects of spinal nerve ligation (SNL) on NTs activation in the lumbar dorsal root.
Ten male Wistar rats were ran­domly assigned to two groups: tight ligation of the L5 spinal nerve (SNL: n=5) and Sham (n=5). In order to produce neuropathic pain, the L5 spinal nerve was tightly ligated (SNL). Then, allodynia and hyperalgesia tests were conducted weekly. After 4 weeks, tissue samples were taken from the two groups for laboratory evaluations. Here, Real-Time PCR quantity method was used for measuring NTs gene expression levels.
SNL resulted in a significant weight loss in the soleus muscle (P The present study provides new evidence that neuropathic pain induced by spinal nerve ligation probably activates NTs and Trk receptors expression in DRG. However, further studies are needed to better elucidate the role of NTs in a neuropathic pain.

Ghrelin is a peptide hormone that has been shown to have numerous central and peripheral effects. The central effects including GH secretion, food intake, and energy homeostasis are partly mediated by Kiss1- KissR signaling pathway. Ghrelin and its receptor are also expressed in the pancreatic islets. Ghrelin is one of the key metabolic factors controlling insulin secretion from the islets of Langerhans. We hypothesize that the inhibitory effect of ghrelin on KiSS-1 and KissR in the islet cells may be similar to the same inhibitory effect of ghrelin in the hypothalamus.
To investigate the effect of ghrelin, we isolated the islets from adult male rats by collagenase and cultured CRI-D2 cell lines. Then, we incubated them with different concentrations of ghrelin for 24 hr. After RNA extraction and cDNA synthesis from both islets and CRI-D2 cells, the relative expression of KiSS-1 and KissR was evaluated by means of real-time PCR. Furthermore, we measured the amount of insulin secreted by the islets after incubation in different concentrations of ghrelin and glucose after 1 hr. Besides, we checked the viability of the cells after 24 hr cultivation.
Ghrelin significantly decreased the KiSS-1 and KissR mRNA transcription in rat islets and CRI-D2 cells. Besides, Ghrelin suppressed insulin secretion from pancreatic beta cells and CRI-D2 cells.
These findings indicate the possibility that KiSS-1 and KissR mRNA expression is mediator of ghrelin function in the islets of Langerhans.

Breast cancer is an important leading cause of death from cancer. Stathmin and tau proteins are regulators of cell motility, and their overexpression is associated with the progression and bad prognosis of breast cancer. Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is the potential inhibitor of tau protein in neurons. This study determines the effect of memantine on breast cancer cell migration and proliferation, tau and stathmin gene expression in cancer cells and its synergistic effect with paclitaxel.
The cell proliferation was evaluated by MTT assay and for this purpose, MCF-7 breast cancer cells were treated with various concentration of memantine (2, 20 and 100 μg/ml). Tau and stathmin mRNA expression was evaluated through quantitative real time RT-PCR method. The migration of cancer cells treated with memantine for 24 hr was compared to non-treated cells using an in vitro transmembrane migration assay.
Incubation of breast cancer cells with memantine resulted in a dose dependent reduction in cell survival (P=0.0001). Paclitaxel (100 nM) showed synergistic effect with memantine (P=0.0001). Memantine significantly decreased tau and stathmin mRNA expression (by RT-PCR), so that 100 µmol/l of memantine decreased tau and stathmin expression by 46% (P=0.0341) and 33% (P=0.043), respectively. Migration of cells was also decreased by memantine (P=0.0001).
The presented data shows that memantine reduced mRNA levels of tau and stathmin proteins and also reduced cellular migration.

Comparative in vivo studies were carried out to determine the adsorption characteristics of amitriptyline (AMT) on activated charcoal (AC) and sodium polystyrene sulfonate (SPS). AC has been long used as gastric decontamination agent for tricyclic antidepressants and SPS has showed to be highly effective on in-vitro drugs adsorption.
Sprague-Dawley male rats were divided into six groups. Group I: control, group II: AMT 200 mg/kg as single dose orally, group III and IV: AC 1g/kg as single dose orally 5 and 30 min after AMT administration respectively, and group 5 and 6: SPS 1 g/kg as single dose orally 5 and 30 min after AMT administration, respectively. 60 min after oral administration of AMT (Tmax of AMT determined in rats), Cmax plasma levels were determined by a validated GC-Mass method.
The Cmax values for groups II to IV were determined as 1.1, 0.5, 0.6, 0.1 and 0.3 µg/ml, respectively.
AC and SPS could significantly reduce Cmax of AMT when administrated either 5 or 30 min after AMT overdose (P

To evaluate the protective effect of erdosteine, an antiapoptotic and antioxidant agent, on torsion–detorsion evoked histopathological changes in experimental ovarian ischemia-reperfusion (IR) injury.
Eighteen female Wistar albino rats were used in control, IR, and IRᇚⲵ (IR-E) groups, (n=6 in each). The IR-E group received the erdosteine for seven days before the induction of torsion/retorsion, (10 mg/kg/days). The IR and IR-E groups were exposed to right unilateral adnexal torsion for 3 hr. Three hours later, re-laparotomy was performed, and the right ovaries were surgically excised. Oxidant and antioxidants levels were determined in serum. The ovarian tissue samples were received and fixed with 10% neutral buffered formalin. The sections were stained with H&E, anti-PCNA, and TUNEL.
The IR group were showed severe acute inflammation, polynuclear leukocytes and macrophages, stromal oedema and haemorrhage. Treatment with erdosteine in rats significantly retained degenerative changes in the ovaryPCNA () cell numbers were significantly decreased in the IR and IR-E groups unlike the control group. However, its numbers were significantly increased in the IR-E group unlike the IR group. TUNEL () cell numbers were significantly increased in the IR group unlike the control and the IR-E groups. In erdosteine treated group, TUNEL () cells were detected significantly less than the IR group (P In conclusion, erdosteine maybe a protective agent for ovarian damage and decreasing lipid peroxidation products and leukocytes aggregation after adnexal torsion in animals.

Alzheimer’s disease (AD) as progressive cognitive decline and the most common form of dementia is due to degeneration of the cholinergic neurons in the brain. Therefore, administration of the acetylcholinesterase (AChE) inhibitors such as donepezil is the first choice for treatment of the AD. In the present study, we focused on the synthesis and anti-cholinesterase evaluation of new donepezil like analogs.
A new series of phthalimide derivatives (compounds 4a-4j) were synthesized via Gabriel protocol and subsequently amidation reaction was performed using various benzoic acid derivatives. Then, the corresponding anti-acetylcholinesterase activity of the prepared derivatives (4a-4j) was assessed by utilization of the Ellman's test and obtained results were compared to donepezil. Besides, docking study was also carried out to explore the likely in silico binding interactions.
According to the obtained results, electron withdrawing groups (Cl, F) at position 3 and an electron donating group (methoxy) at position 4 of the phenyl ring enhanced the acetylcholinesterase inhibitory activity. Compound 4e (m-Fluoro, IC50 = 7.1 nM) and 4i (p-Methoxy, IC50 = 20.3 nM) were the most active compounds in this series and exerted superior potency than donepezil (410 nM). Moreover, a similar binding mode was observed in silico for all ligands in superimposition state with donepezil into the active site of acetylcholinesterase.
Studied compounds could be potential leads for discovery of novel anti-Alzheimer agents in the future.

Every year, a large number of people lose their lives due to stroke. Stroke is the second leading cause of death worldwide. Surprisingly, recent studies have shown that preconditioning with hyperoxia (HO) increases tissue tolerance to ischemia, ultimately reducing damages caused by stroke. Addressed in this study are beneficial contributions from HO preconditioning into reduced harm to be incurred by the attack, as well as its effect on the expression levels of vascular endothelial growth factor (VEGF) and endostatin.
A set of experiments was conducted where a number of rats were divided into three groups. The animals in the first group received 90% oxygen for 4 hr a day, for 6 days. The second group was housed in room air and the third group was a sham (surgical stress). After 60 min of ischemia, 24 hr blood flow, neurological deficit score (NDS) and infarct volume (IV) in the group MCAO (Middle Cerebral Artery Occlusion) were investigated. Immediately following a 48 hr HO pre-treatment, sampling was performed to measure the expression levels of VEGF and endostatin.
Preconditioning with alternating HO led to reduced infarct volume and NDS. Moreover, pre-treatment with HO resulted in increased VEGF expression while decreasing endostatin.
Although further studies are deemed necessary to clarify the mechanisms of ischemic tolerance, apparently, somewhat intermittent hyperoxia can be associated with positive impacts by increasing VEGF and decreasing expression of endostatin.

Global cerebral ischemia-reperfusion (GCIR) causes disturbances in brain functions as well as other organs such as kidney. Our aim was to evaluate the protective effects of ellagic acid (EA) on certain renal disfunction after GCIR.
Adult male Wistar rats (n=32, 250-300 g) were used. GCIR was induced by bilateral vertebral and common carotid arteries occlusion (4-VO). Animal groups were: 1) received DMSO/saline (10%) as solvent of EA, 2) solvent GCIR, 3) EA GCIR, and 4) EA. Under anesthesia with ketamine/xylazine, GCIR was induced (20 and 30 min respectively) in related groups. EA (100 mg/kg, dissolved in DMSO/saline (10%) or solvent was administered (1.5 ml/kg) orally for 10 consecutive days to the related groups. EEG was recorded from NTS in GCIR treated groups.
Our data showed that: a) EEG in GCIR treated groups was flattened. b) GCIR reduced GFR (P Results indicate that GCIR impairs certain renal functions and EA as an antioxidant can improve these functions. Our results suggest the possible usefulness of ellagic acid in patients with brain stroke.

To understand the role of mitochondrial respiration in cisplatin sensitivity, we have employed wild-type and mitochondrial DNA depleted Rho0 yeast cells.
Wild type and Rho0 yeast cultured in fermentable and non-fermentable sugar containing media, were studied for their sensitivity against cisplatin by monitoring growth curves, oxygen consumption, pH changes in cytosol/mitochondrial compartments, reactive oxygen species production and respiratory control ratio.
Wild-type yeast grown on glycerol exhibited heightened sensitivity to cisplatin than yeast grown on glucose. Cisplatin (100 μM), although significantly reduced the growth of wild- type cells, only slightly altered the growth rate of Rho0 cells. Cisplatin treatment decreased both pHcyt and pHmit to a similar extent without affecting the pH difference. Cisplatin dose-dependently increased the oxidative stress in wild-type, but not in respiration-deficient Rho0 strain. Cisplatin decreased the respiratory control ratio.
These results suggest that cisplatin toxicity is influenced by the respiratory capacity of the cells and the intracellular oxidative burden. Although cisplatin per se slightly decreased the respiration of yeast cells grown in glucose, it did not disturb the mitochondrial chemiosmotic gradient.

Previous studies showed that skeletal muscle microcirculation was reduced in chronic heart failure. The aim of this study was to investigate the effects of endurance training on capillary and arteriolar density of fast and slow twitch muscles in rats with chronic heart failure.
Four weeks after surgeries (left anterior descending (LAD) artery occlusion), chronic heart failure rats were divided into 3 groups: Sham (Sham, n=10); Sedentary (Sed, n=10); Exercise training (Ex, n=10). Ex group rats were subjected to endurance training in the form of treadmill running with moderate intensity for 10 weeks.
Exercise training significantly increased capillary density and capillary to fiber ratio (P Endurance training ameliorates fast and slow twitch muscle revascularization non-uniformly in chronic heart failure rats by increasing capillary density in slow twitch muscle and arteriolar density in fast twitch muscle. The difference in revascularization at slow and fast twitch muscles may be induced by the difference in angiogenic and angiostatic gene expression response to endurance training.

Inflammation is an immune response toward injuries. Although inflammation is healing response, but in some condition it will lead to chronic disease such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, Alzheimer’s and various cancer. Indonesian cassia (Cinnamomum burmanni C. Nees & T. Ness) known to contain coumarin, is widely used for alternative medicine especially as an antiinflammator.This study was conducted to determine the anti-inflammatory properties of coumarin and Indonesian cassia extract (ICE) in LPS-induced RAW264.7 cell line.
The cytotoxic assay of coumarin and ICE against RAW264.7 cells was conducted using MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium). The anti-inflammatory potential was determined using LPS-induced RAW 267.4 macrophages cells to measure inhibitory activity of both compounds on production of nitric oxide (NO), prostaglandin E2 (PGE2), and also cytokines such as interleukin-6 (IL-6), interleukin-1β (IL-1β) and TNF-α.
Coumarin 10 µM and ICE 10 µg/ml were nontoxic to the RAW264.7 cells. Both of coumarin and ICE were capable to reduce the PGE2, TNF-α, NO, IL-6, and IL-β level in LPS-induced RAW264.7 cells. Coumarin had higher activity to decrease PGE2 and TNF-α, whilst ICE had higher activity to inhibit NO, IL-6, and IL-β levels.
Coumarin and ICE possess anti-inflammatory properties through inhibition of PGE2 and NO along with pro-inflammatory cytokines TNF-α, IL-6, IL-1β production.