Natural products, PGC-1 , and Duchenne muscular dystrophy

Peroxisome proliferator-activated receptor (PPAR) is a transcriptional coactivator that binds to a diverse range of transcription factors. PPAR coactivator 1 (PGC-1) coactivators possess an extensive range of biological effects in different tissues, and play a key part in the regulation of the oxidative metabolism, consequently modulating the production of reactive oxygen species, autophagy, and mitochondrial biogenesis. Owing to these findings, a large body of studies, aiming to establish the role of PGC-1 in the neuromuscular system, has shown that PGC-1 could be a promising target for therapies targeting neuromuscular diseases. Among these, some evidence has shown that various signaling pathways linked to PGC-1 are deregulated in muscular dystrophy, leading to a reduced capacity for mitochondrial oxidative phosphorylation and increased reactive oxygen species (ROS) production. In the light of these results, any intervention aimed at activating PGC-1 could contribute towards ameliorating the progression of muscular dystrophies. PGC-1 is influenced by different patho-physiological/pharmacological stimuli. Natural products have been reported to display modulatory effects on PPAR activation with fewer side effects in comparison to synthetic drugs. Taken together, this review summarizes the current knowledge on Duchenne muscular dystrophy, focusing on the potential effects of natural compounds, acting as regulators of PGC-1.

Melatonin pretreatment enhances the homing of bone marrow-derived mesenchymal stem cells following transplantation in a rat model of liver fibrosis

Background: Bone marrow-derived mesenchymal stem cells [BMMSCs] transplantation has been considered as a promising milestone in liver fibrosis treatment. However, low amounts of homing are a major obstacle. We aimed to investigate the role of melatonin pretreatment in BMMSC homing into experimental liver fibrosis

Methods: BMMSCs were obtained, grown, propagated and preconditioned with 5 µM melatonin and analyzed for multipotency and immunophenotypic features at passage three. The cells were labelled with CM-Dil and infused into the rats received the i.p. injection of carbon tetrachloride [CCl4] for five weeks to induce liver fibrosis. Animals were divided into two groups: One group received BMMSCs, whereas the other group received melatonin-pretreated BMMSCs [MT-BMMSCs]. After cell injection at 72 h, animals were sacrificed, and the liver tissues were assessed for further evaluations: fibrosis using Masson's trichrome and hematoxylin and eosin staining and homing using fluorescent microscopy and flow cytometry

Results: BMMSCs and MT-BMMSCs expressed a high level of CD44 but low levels of CD11b, CD45 and CD34 [for all P

Conclusion: This study indicates the improved homing potential of BMMSCs in pretreatment with melatonin. Therefore, this strategy may represent an applied approach for improving the stem cell therapy of liver fibrosis

Role of somatic testicular cells during mouse spermatogenesis in three-dimensional collagen gel culture system

Spermatogonial stem cells [SSCs] are the only cell type that can restore fertility to an infertile recipient following transplantation. Much effort has been made to develop a protocol for differentiating isolated SSCs in vitro. Recently, three-dimensional [3D] culture system has been introduced as an appropriate microenvironment for clonal expansion and differentiation of SSCs. This system provides structural support and multiple options for several manipulation such as addition of different cells. Somatic cells have a critical role in stimulating spermatogenesis. They provide complex cell to cell interaction, transport proteins and produce enzymes and regulatory factors. This study aimed to optimize the culture condition by adding somatic testicular cells to the collagen gel culture system in order to induce spermatogenesis progression. In this experimental study, the disassociation of SSCs was performed by using a two-step enzymatic digestion of type I collagenase, hyaluronidase and DNase. Somatic testicular cells including Sertoli cells and peritubular cells were obtained after the second digestion. SSCs were isolated by Magnetic Activated Cell Sorting [MACS] using GDNF family receptor alpha-1 [Gfr Alpha -1] antibody. Two experimental designs were investigated. 1. Gfr Alpha -1 positive SSCs were cultured in a collagen solution. 2. Somatic testicular cells were added to the Gfr Alpha -1 positive SSCs in a collagen solution. Spermatogenesis progression was determined after three weeks by staining of synaptonemal complex protein 3 [SCP3]-positive cells. Semi-quantitative Reverse Transcription PCR was undertaken for SCP3 as a meiotic marker and, Crem and Thyroid transcription factor-1 [TTF1] as post meiotic markers. For statistical analysis student t test was performed Testicular supporter cells increased the expression of meiotic and post meiotic markers and had a positive effect on extensive colony formation. Collagen gel culture system supported by somatic testicular cells provides a microenvironment that mimics seminiferous epithelium and induces spermatogenesis in vitro

[Evaluation of the protective effects of quercetin in biliary cirrhotic rats]

Biliary cirrhosis is a chronic disease marked by the progressive destructtion of liver. There is no known cure for this disease; however, medications may slow its progression. The present study was designed to investigate the effect of quercetin as a plant derived flavonoid on the hepatic injury reduction of biliary cirrhotic rats. Thirty male Sprague-Dawley rats aged 6-7 months were randomized into three groups of ten each. One group served as control [sham operated], while the other two groups underwent a complete bile-duct ligation [BDL]. Four weeks after the operation, serum bilirubin, alkaline phosphatase [ALP], alanine amino-transferase [ALT], and aspartate amino-transferase [AST] were measured in two BDL groups to confirm the occurrence of cirrhosis. Then one of the BDL groups received placebo and the other one injected intraperitoneally with 50 mg/kg of quercetin once a day for a period of four weeks. At the end of the study, hepatic enzymes and serum bilirubin were measured again. Liver species were tested for histological characteristics. Quercetin could decrease serum level of bilirubin [7.4 +/- 0.9 vs.8.9 +/- 1.6 mg/dL; P<0.05], ALP [1387 +/- 76.9 vs.2273 +/- 65.3 IU/L; P<0.001] and ALT [601.9 +/- 38.1 vs.644.8 +/- 37.4 IU/L; P<0.05] compared to cirrhotic group. AST was higher in cirrhotic groups compared to control both in the 4[th] and 8[th] week. However, the difference between BDL and BDL+Q groups was not statistically significant. Quercetin decreased ALT/AST ratio, as an indicator of liver damage. No significant histological changes were observed in quercetin group. These data suggest that although quercetin did not change histological characteristics of liver, it could significantly decrease bilirubin, alkaline phosphatase and alanine amino-transferase, indicating less liver injury

Medical podcasting in Iran; pilot, implementation and attitude evaluation

Podcasting has become a popular means of transferring knowledge in higher education through making lecture contents available to students at their convenience. Accessing courses on media players provides students with enhanced learning opportunities. Development of teaching methods able to cope with ever-changing nature of medicine is crucial to train the millennium students. Pharmacology education in Tehran University of Medical Sciences has been based on lectures so far; our aim was to implement a pilot study to evaluate the advantages and disadvantages of offering the course contents as podcasts as well as evaluating whether such program can be feasible in our educational program. 46% of students downloaded the podcast according to our download center. 48% favored usage of both internet and DVD-ROM concurrently. Overall 96% of students perceived that podcasting had a positive impact on their learning in pharmacology course. Our results indicate that most of attendants proposed the positive yields of podcasting despite low usage of it, mainly as a pre-class preparing tool

Sleep-related eating disorder: a case report of a progressed night eating syndrome

Night eating syndrome is a common disorder in eating behaviors that occurs in close relation to the night time sleep cycle. Although eating disorders are common in society, night eating syndrome has been left neglected by health care professionals. In this report we present a case of eating disorder that exhibits some novel features of night eating syndrome. Our case was a progressed type of eating disorder which may increase awareness among physicians about sleep-related eating disorders.

Effect of topical application of silymarin [silybum marianum] on excision wound healing in albino rats

Silymarin, an extract from Silybum marianum, has been shown to have antioxidant properties. However, there is no scientific report on wound healing activity of the silymarin. The purpose of this study was to evaluate the effect of topical administration of silymarin on excision wound healing in rats. Excision wounds were made on the back of rats. Rats were divided into three groups, as control, vehicle, and treatment. Vehicle and treatment groups received polyethylene glycol and silymarin dissolved in polyethylene glycol, respectively. The control group did not receive any treatment. The wound tissues were removed on 5th, 10th and 15th day for histopathological analysis and total collagen determination by hydroxyproline assay. Results showed that silymarin increased epithelialization and decreased inflammation but did not have any effect on percentage of wound contraction, collagenization and hydroxyproline levels. It was concluded that silymarin can significantly stimulate epithelialization and reduce inflammation in full-thickness wounds in rats.

Effect of aqueous extract of elaeagnus angustifolia fruit on experimental cutaneous wound healing in rats

The present study was conducted to investigate the histological changes and wound healing effect of aqueous extract of Elaeagnus angustifolia. After creating full-thickness skin wounds on the back of 45 male Sprague-Dawley rats they were randomly divided into three groups. Treated group received the extract, positive control group were treated with mupirocin ointment 2% and control group did not receive any treatment. Wound healing rates were calculated on days 3, 5, 8, 10, 12 and 15 post-wounding and the wound tissues were harvested at 5, 10, and 15 days for histological analysis and hydroxyproline content measurement. The results indicated a significant increase in the percentage of wound contraction and hydroxyproline content in the treated group comparing to the control and positive control groups. A significant increase in the assigned histological scores was observed at 10 and 15 days in the treated and positive control groups compared to the control group. The results demonstrate that aqueous extract of Elaeagnus angustifolia accelerates cutaneous wound healing, and its effect may be due to the increased reepithelialization and collagen deposition in wound and so it can be considered as a therapeutic agent for wound healing.

Effects of lithium on peripheral neuropathy induced by vincristine in rats

Vincristine [VCR] as a frequently used antimitotic agent which is commonly prescribed for wide spectrum of neoplasm, causes mixed sensorimotor neuropathy. Several evidences show lithium could be a neuroprotective agent, therefore to assess whether a pretreatment and at subtherapeutic dose it could prevent the peripheral neuropathy produced by VCR, rats were treated with VCR 0.1mg/kg i.p. for 3 alternative doses and / or lithium chloride [20mg/kg or 40 mg/kg i.p. daily from the first day to the day of sacrifice]. Erythrocyte lithium concentration [ELC] and plasma lithium concentration [PLC] were measured at the seventh day of study and the day of scarification. After seventh day of lithium administration, PLC and ELC reached to a steady state at subtherapeutic dose and they did not significantly change at normal housing situation. Hot plate, open field test and nerve conduction velocity were used to evaluate the sensory and motor neuropathy. Only VCR treated rats showed behavioral, electrophysiological and histological evidences of a mixed sensorimotor neuropathy by significant increase in hot plate latencies and a marked decrease in total distance moved and conduction velocities in both sensory and motor nerves. Lithium at the dose of 20mg/kg and specially 40mg/kg robustly reduced the rate of mortality, general toxicity and was able to ameliorate mixed sensorimotor neuropathy induced by VCR. These results suggest that lithium at dose of 20mg/kg and 40 mg/kg, potentially by its effects on cell survival pathways such as inhibition of glycogen synthase kinase-3 [GSK3beta], can prevent both motor and sensory components of VCR neuropathy

effects of cholestasis and cirrhosis on gastric acid and pepsin secretions in rat: involvement of Nitric Oxide

The liver has major role in the organism homeostasis, interactions with other systems, synthesis and metabolism of bile production, drug detoxification and hormone inactivation. Cholestasis can be defined as an impairment of the bile flow which can lead to hepatocytes necrosis and finally cirrhosis. Some studies reported a gastric acid secretion reduction in cirrhotic subjects, while others reported normal production gastric acid secretion. Our aim was to evaluate the effects of cholestasis and cirrhosis on gastric acid and pepsin secretions and its possible mechanism in rat. Male Wistar rats were randomly divided into five groups [n=8]: control, cholestasis, sham cholestasis, cirrhosis and sham cirrhosis. Laparotomy was done under general anesthesia and then bile duct ligation [BDL] was performed. After 2 and 4 weeks in cholestasis and cirrhosis groups respectively, gastric content was collected by wash-out technique. Basal and stimulated acid an pepsin secretions were measured by using titration and the Anson method respectively in all groups. In order to measure stimulated acid and pepsin secretions, pentagastrin [25 micro g/kg, i.p.] was used. Nitric Oxide [NO] metabolites of gastric tissue were determined by Griess microassy method. Acid and pepsin secretions were significantly reduced in cholestatic and cirrhotic rats in comparison with control and sham groups [P< 0.01]. NO metabolite of gastric tissue was significantly increased in cholestatic and cirrhotic rats [P> 0.01]. Reducing of gastric acid and pepsin output in cholestatic and cirrhotic rats may be due to increasing in NO content of gastric tissue

[Role of ATP-sensitive potassium channels in the clonic seizure threshold induced by pentylenetetrazole in mice with diabetes type I]

Although there is evidence that diabetes affects seizure susceptibility, the underlying mechanism has not been completely understood. On the other hand, several studies have suggested a pivotal role for K[ATP] channels in the seizure modulation. So, the present study was designed to evaluate the seizure threshold induced by pentylenetetrazole [PTZ] in diabetic mice at different times and to examine the possible role of ATP-sensitive potassium [K[ATP]] channels. In this experimental study, NMRI were diabetic with streptozocine. Then clonic seizure thresholds were determined at different times after induction of diabetes compared with corresponding non-diabetic groups. Each experimental group consisted of ten mice. There was a time-dependent alteration in the threshold in diabetic mice, reaching a peak on week 2 after STZ injection and declining significantly afterwards. The seizure threshold in 8-week diabetic mice was even lower than control levels, though the difference was not significant. The non-effective dose of K[ATP] channel blocker glibenclamide [1 mg/kg, i.p.], but not the voltage-dependent K+ channel blocker 4-aminopyridine [1 mg/kg, i.p.], decreased the seizure threshold in 2-week diabetic mice to the control levels which was blocked by pre-treatment with the K[ATP] channel opener cromakalim [10 micro g/kg, i.p.]. Moreover, the non-effective dose of cromakalim [10 micro g/kg, i.p.] increased significantly the seizure threshold in 8-week diabetic mice which was inhibited by pre-treatment with glibenclamide [1 mg/kg, i.p.] but not with 4-aminopyridine [1 mg/kg, i.p.]. This study indicated that the PTZ-induced seizure threshold is altered in diabetic mice in a time-dependent manner which could be due to the probable alteration in the K[ATP] channel functioning during diabetes

Induction of liver metallothionein contribute to the developmental toxicity of valproic acid in rat

There is an increased risk of neural tube defects and axial skeletal malformations among infants born by mothers who had received valproic acid. The aim of the present study is, if administration of valproic acid can induce maternal hepatic Metallothionein [MT] synthesis and so secondary decrease of plasma Zn. In the present experimental study, mated rats were divided into four groups of 12 animals each [control, valproic acid [VPA], valproic acid + zinc [VPA+ Zn] and Zinc [Zn] groups. The VPA group received 300 mg/kg valproic acid; daily. The control group received an equal volume of 0.9% NaCI. The VPA+ Zn group received 300 mg/kg VPA as well as 30 mg/kg zinc sulfate, and the Zn group received 30 mg/kg zinc sulfate, daily. These drugs were administered intraperitoneally from day 6 through day 15 of gestation. Dams were killed on GD 16 or 20. Blood was drawn to determine plasma zinc; furthermore, maternal liver Zn and MT were also determined. The zinc concentration in the plasma of rats treated with valproic acid was significantly lower than those of the other groups on GD 16 [p=0.004], but liver Zn [p=0.016] and MT [p=0.004] were significantly higher than those of the control group. On GD 20 the incidence of skeletal malformations and neural tube defects tended to be higher in VPA group than VPA+ Zn treated group and no anomalies were seen in the control group. The results from the present experiment support hypothesis that one of biochemical lesions causing the teratogenicity of VPA is a drug -induced maternal plasma zinc deficiency secondary to Metallothionein induction in liver