Antimicrobial properties of Teucrium polium against some clinical pathogens

ObjectiveTo explore the antibacterial effect of the alcoholic extracts of aerial parts of Teucrium polium, native in Iran on some pathogenic bacteria.MethodsAntibacterial activity of ethanolic extract (50 to 400 mg/mL) and methanolic extract (400 and 600 mg/mL) was evaluated by disc diffusion method.ResultsThe ethanolic extract results showed that Bacillus anthracis was the most sensitive species, while Escherichia coli and Proteus mirabilis were more resistant than others. In the case of the methanolic extract, Bordetella bronchiseptica was the most sensitive and Proteus mirabilis and Arcanobacterium pyogenes were the most resistant species. The hydroalcoholic extract of Teucrium polium had a relatively satisfactory effect on Salmonella typhi. The minimal inhibitory concentration (MIC) of Staphylococcus aureus and Salmonella typhi was 40 mg/mL and Bordetella bronchiseptica and Bacillus anthracis was 10 mg/mL. The minimal bactericidal concentration (MBC) against Bacillus anthracis was 10 mg/mL while against other species were not found (>200 mg/mL). The methanolic extract had also synergistic effect with methicillin, vancomycin against Staphylococcus aureus and with novobiocin against Salmonella typhi.ConclusionsThese results suggest that this plant contains relatively good antibacterial activity and it can be used as a source of antiseptic compounds for medicinal uses.     

4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase

A new series of MEK1 inhibitors, the 4-anilino-5-carboxamido-2-pyridones, were designed and synthesized using a combination of medicinal chemistry, computational chemistry, and structural elucidation. The effect of variation in the carboxamide side chain, substitution on the pyridone nitrogen, and replacement of the 4'-iodide were all investigated. This study afforded several compounds which were either equipotent or more potent than the clinical candidate CI-1040 (1) in an isolated enzyme assay, as well as murine colon carcinoma (C26) cells, as measured by suppression of phosphorylated ERK substrate. Most notably, pyridone 27 was found to be more potent than 1 in vitro and produced a 100% response rate at a lower dose than 1, when tested for in vivo efficacy in animals bearing C26 tumors.     

Androgen-dependent pathology demonstrates myopathic contribution to the Kennedy disease phenotype in a mouse knock-in model

Kennedy disease, a degenerative disorder characterized by androgen-dependent neuromuscular weakness, is caused by a CAG/glutamine tract expansion in the androgen receptor (Ar) gene. We developed a mouse model of Kennedy disease, using gene targeting to convert mouse androgen receptor (AR) to human sequence while introducing 113 glutamines. AR113Q mice developed hormone and glutamine length-dependent neuromuscular weakness characterized by the early occurrence of myopathic and neurogenic skeletal muscle pathology and by the late development of neuronal intranuclear inclusions in spinal neurons. AR113Q males unexpectedly died at 2-4 months. We show that this androgen-dependent death reflects decreased expression of skeletal muscle chloride channel 1 (CLCN1) and the skeletal muscle sodium channel alpha-subunit, resulting in myotonic discharges in skeletal muscle of the lower urinary tract. AR113Q limb muscles show similar myopathic features and express decreased levels of mRNAs encoding neurotrophin-4 and glial cell line-derived neurotrophic factor. These data define an important myopathic contribution to the Kennedy disease phenotype and suggest a role for muscle in non-cell autonomous toxicity of lower motor neurons.     

First National Report on Aminotransaminases’ Percentiles in Children of the Middle East and North Africa (MENA): the CASPIAN-III Study

Background

By the current global obesogenic environment, non-alcoholic fatty liver disease is becoming an important health problem in the pediatric age group.

Objectives

This study aimed to determine the first age-and gender-specific percentiles and upper limit normal limit (ULN) of alanine aminotransaminase (ALT) and aspartate aminotransaminase (AST) among a nationally-representative sample of children and adolescents in the Middle East and North Africa (MENA). The second objective was to determine the linear association of obesity indexes and age with serum ALT and AST levels.

Patients and Methods

This nationwide study was conducted among a representative sample of 4078 students aged 10-18 years, who were selected by multistage random cluster sampling from 27 provinces of Iran. ALT and AST were measured on fresh sera. Body mass index (BMI) was calculated as an index of generalized obesity, and waist- to- height ratio (WHtR) as an index of abdominal obesity. The age- and gender-specific percentiles of ALT and AST were constructed, and the 95th percentile of each enzyme was considered as the ULN. Gender-specific linear regression analysis was employed to examine the association of BMI or WHtR with the levels of ALT and AST.

Results

Data of ALT and AST were available for 4078 (2038 girls) and 4150 (2061 girls),respectively. Participants had a mean (SD) age of 14.71 (2.41).The ULN of ALT for boys, girls,and the total individuals were 36.00; 38.00; and, 37.00 U/L, respectively. In both genders, ALT and AST had linear association with age. The association with BMI was significant for ALT in both genders and for AST only in boys, the association of ALT with WHtR was significant in both genders; the corresponding figures were not significant for AST.

Conclusions

The findings of the current study confirmed the current ULN value of 40 U/L commonly used for the pediatric age group. The linear association of indexes for generalized and abdominal obesity with ALT underscores the importance of timely prevention and control of childhood obesity.     

Association of AKT1 haplotype with the risk of schizophrenia in Iranian population.

AKT-glycogen synthase kinase 3beta (GSK3beta) signaling is a target of lithium and has been implicated in the pathogenesis of mood disorders and schizophrenia. AKT1 protein level is decreased in the peripheral lymphocytes and brains of schizophrenic patients. The SNP2/3/4 TCG haplotype of AKT1 was associated with schizophrenia in patients with Northern European origin. In the present study, we genotyped five single nucleotide polymorphisms (SNP1-5) of AKT1 gene according to the original study in Iranians comprising of 321 schizophrenic patients and 383 controls, all residing in Mashhad city, Northeastern Iran. Haplotype analysis showed that the frequency of a five-SNP haplotype (AGCAG) was significantly higher in schizophrenic patients (0.068) than that of controls (0.034) (P = 0.03 after Bonferroni correction, OR = 2.04, CI = 1.2-3.4). In stratified analysis by schizophrenia subtypes, the frequency of the same haplotype was significantly higher in disorganized subtype (n = 78, frequency of haplotype=0.081) when compared with normal controls (P = 0.04 after Bonferroni correction, OR = 2.59, CI = 1.3-5.2). Our findings did not confirm the association of AKT1 SNP2/3/4 TCG haplotype with the risk of schizophrenia as reported in the original study but showed the evidence of association with a different haplotype, AKT1 five-SNP AGCAG haplotype, with the risk of schizophrenia in Iranian population.     

Cerebral state index versus Glasgow coma scale as a predictor for in-hospital mortality in brain-injured patients

Objective：To compare the value of Glasgow coma scale （GCS） and cerebral state index （CSI）on predicting hospital discharge status of acute braininjured patients.Methods：In 60 brain-injured patients who did not receive sedatives,GCS and CSI were measured daily during the first 10 days of hospitalization.The outcome of prognostic cut-off points was calculated by GCS and CSI using receiver operating characteristic （ROC） curve regarding the time of admission and third day of hospitalization.Sensitivity,specificity and other predictive values for both indices were calculated.Results：Of the 60 assessed patients,14 patients had mild,13 patients had moderate and 33 patients had severe injuries.During the course of the study,17 patients （28.3％） deteriorated in their situation and died.The mean GCS and CSI in patients who deceased during hospitalization was significantly lower than those who were discharged from the hospital.GCS＜4.5 and CSI＜64.5 at the time of admission was associated with higher mortality risk in traumatic brain injury patients and GCS was more sensitive than CSI to predict in-hospital death in these patients.For the first day of hospitalization,the area under ROC curve was 0.947 for GCS and 0.732 for CSI.Conclusion：GCS score at ICU admission is a good predictor of in-hospital mortality.GCS＜4.5 and CSI＜64.5 at the time of admission is associated with higher mortality risk in traumatic brain injury patients and GCS is more sensitive than CSI in predicting death in these patients.     

Synthesis,radiolabeling and bioevaluation of a novel arylpiperazine derivative containing triazole as a 5-HT1A receptor imaging agents

IntroductionIt has been recognized that serotonin plays a main role in various pathological conditions such as anxiety, depression, aggressiveness, schizophrenia, suicidal behavior, panic and autism. 1-(2-Methoxyphenyl) piperazine pharmacophore, a fragment of the true 5-HT_1A antagonist WAY100635, is found in numerous selective 5-HT_1A imaging agents. In this paper, we have reported the synthesis of a novel derivative of 1-(2-methoxyphenyl) piperazine that is labeled with ^99mTc (CO)₃ via click chemistry.MethodsThe bidentate alkyne, propargylglycine was reacted with phenyl piperazine triazole derivative in the presence of a catalytic amount of Cu (I) to form tridentate ligand. The ligand was radiolabeled with the precursor [^99mTc] [(H₂O)₃ (CO)₃]⁺ and characterized by HPLC. The bioevaluation of radio labeled ligand was carried out in rats.ResultsTriazole complex was labeled by ^99mTc-tricarbonyl and its radiochemical yield was more than > 95% which was determined by HPLC. In vivo stability studies in human serum albumin show a 93% ratio of complex after a 24 h period. The calculated partition coefficient (logP) was 0.34 ± 0.02. Receptor binding assays indicated about 70% specific binding of radioligand to 5-HT_1A receptors. Biodistribution studies have shown brain hippocampus uptake of 0.40 ± 0.08 %ID/g at 30 min post injection.ConclusionsResults indicate that this ^99mTc-tricabonyl-arylpiperazine derivative has specific binding to 5-HT_1A receptors and presented suitable characters for its use as a CNS imaging agent.     

Pathogenic mechanisms following ischemic stroke

Stroke is the second most common cause of death and the leading cause of disability worldwide. Brain injury following stroke results from a complex series of pathophysiological events including excitotoxicity, oxidative and nitrative stress, inflammation, and apoptosis. Moreover, there is a mechanistic link between brain ischemia, innate and adaptive immune cells, intracranial atherosclerosis, and also the gut microbiota in modifying the cerebral responses to ischemic insult. There are very few treatments for stroke injuries, partly owing to an incomplete understanding of the diverse cellular and molecular changes that occur following ischemic stroke and that are responsible for neuronal death. Experimental discoveries have begun to define the cellular and molecular mechanisms involved in stroke injury, leading to the development of numerous agents that target various injury pathways. In the present article, we review the underlying pathophysiology of ischemic stroke and reveal the intertwined pathways that are promising therapeutic targets.     

Functional inactivation of orexin 1 receptors in CA1 region impairs acquisition, consolidation and retrieval in Morris water maze task

Orexin containing neurons in the lateral hypothalamic area (LHA) produce orexin-A (hypocretin-1) and orexin-B (hypocretin-2) and send their axons to the hippocampus, which predominantly expresses orexin 1 receptors (OX1Rs) showing a higher affinity to orexin-A. Recent studies have shown that central administration of orexin-A has an effect on learning and memory but literature concerning the role of orexinergic system in cognition remains controversial. Therefore, we examined the effect of pre-training, post-training and pre-probe trial intrahippocampal CA1 administration of a selective OX1R the orexin 1 receptor antagonist SB-334867-A (1.5, 3, 6 microg/0.5 microl) on acquisition, consolidation and retrieval in a single-day testing version of Morris water maze (MWM) task. Our results show that, SB-334867-A impaired acquisition, consolidation and retrieval of MWM task as compared with the control group. This drug had no effect on escape latency of a non-spatial visual discrimination task. Therefore, it seems that endogenous orexins, especially orexin-A, play an important role in spatial learning and memory in the rat.