Gap junction blockers: a potential approach to attenuate morphine withdrawal symptoms

Background

The exact mechanisms of morphine-induced dependence and withdrawal symptoms remain unclear. In order to identify an agent that can prevent withdrawal syndrome, many studies have been performed. This study was aimed to evaluate the effect of gap junction blockers; carbenoxolone (CBX) or mefloquine (MFQ); on morphine withdrawal symptoms in male rat.Adult male Wistar rats (225 – 275 g) were selected randomly and divided into 10 groups. All groups underwent stereotaxic surgery and in order to induce dependency, morphine was administered subcutaneously) Sc) at an interval of 12 hours for nine continuous days. On the ninth day of the experiment, animals received vehicle or CBX (100, 400, 600 μg/10 μl/rat, icv) or MFQ (50, 100 and 200 μg/10 μl/rat, icv) after the last saline or morphine (Sc) injection. Morphine withdrawal symptoms were precipitated by naloxone hydrochloride 10 min after the treatments. The withdrawal signs including: jumping, rearing, genital grooming, abdomen writhing, wet dog shake and stool weight, were recorded for 60 minutes.

Results

Results showed that CBX and MFQ decreased all withdrawal signs; and the analysis indicated that they could attenuate the total withdrawal scores significantly.

Conclusion

Taking together it is concluded that gap junction blockers prevented naloxone-precipitated withdrawal symptoms.     

Synthesis,cyclooxygenase inhibitory effects,and molecular modeling study of 4-aryl-5-(4-(methylsulfonyl)phenyl)-2-alkylthio and -2-alkylsulfonyl-1H-imidazole derivatives

A series of 4-aryl-5-(4-(methylsulfonyl)phenyl)-2-alkylthio and 2-alkylsulfonyl-1H-imidazole derivatives were synthesized. All compounds were tested in human blood assay to determine COX-1 and COX-2 inhibitory potency and selectivity. Among the synthesized compounds, 2-alkylthio series were more potent and selective than 2-sulfonylalkyl derivatives. In molecular modeling, interaction of 2-sulfonylalkyl moiety with Arg120 in COX-1 and an extra hydrogen bond with Tyr341 in COX-2 increased the residence time of ligands in the active site in 2-sulfonylalkyl and 2-alkylthio analogs, respectively.     

Establishment and Biological Characterization of a Panel of Glioblastoma Multiforme (GBM) and GBM Variant Oncosphere Cell Lines

Objective

Human tumor cell lines form the basis of the majority of present day laboratory cancer research. These models are vital to studying the molecular biology of tumors and preclinical testing of new therapies. When compared to traditional adherent cell lines, suspension cell lines recapitulate the genetic profiles and histologic features of glioblastoma multiforme (GBM) with higher fidelity. Using a modified neural stem cell culture technique, here we report the characterization of GBM cell lines including GBM variants.

Methods

Tumor tissue samples were obtained intra-operatively and cultured in neural stem cell conditions containing growth factors. Tumor lines were characterized in vitro using differentiation assays followed by immunostaining for lineage-specific markers. In vivo tumor formation was assayed by orthotopic injection in nude mice. Genetic uniqueness was confirmed via short tandem repeat (STR) DNA profiling.

Results

Thirteen oncosphere lines derived from GBM and GBM variants, including a GBM with PNET features and a GBM with oligodendroglioma component, were established. All unique lines showed distinct genetic profiles by STR profiling. The lines assayed demonstrated a range of in vitro growth rates. Multipotency was confirmed using in vitro differentiation. Tumor formation demonstrated histologic features consistent with high grade gliomas, including invasion, necrosis, abnormal vascularization, and high mitotic rate. Xenografts derived from the GBM variants maintained histopathological features of the primary tumors.

Conclusions

We have generated and characterized GBM suspension lines derived from patients with GBMs and GBM variants. These oncosphere cell lines will expand the resources available for preclinical study.     

Relationship between myocardial bridge compression severity and haemodynamic perturbations

Objectives: This study aims to examine the alteration in coronary haemodynamics with increasing the severity of vessel compression caused by myocardial bridging (MB).

Methods: Angiography and intravascular ultrasound were performed in 10 patients with MB with varying severities of systolic compression in the left anterior descending (LAD) artery. Computer models of MB were developed and transient computational fluid dynamics simulations were performed to derive distribution of blood residence time and shear stress.

Results: With increasing the severity of bridge compression, a decreasing trend was observed in the shear stress over proximal segment whereas an increasing trend was found in the shear stress over bridge segment. When patients were divided into 2 groups based on the average systolic vessel compression in the whole cohort (%CR_ave = 27.38), patients with bridges with major systolic compression (>%CR_ave) had smaller shear stress and higher residence time in the proximal segment compared to those with bridges with minor systolic compression (<%CR_ave) (0.37?±?0.23 vs 0.69?±?0.29?Pa and 0.0037?±?0.0069 vs 0.022?±?0.0094?s). In contrast, patients with bridges with major systolic compression had greater shear stress in the bridge segment compared to those with bridges with minor systolic compression (2.49?±?2.06 vs 1.13?±?0.89?Pa). No significant difference was found in the distal shear stress of patients with bridges with major and minor systolic compression.

Conclusion: Our findings revealed a direct relationship between the severity of systolic compression of MB and haemodynamic perturbations in the proximal segment such that the increased systolic vessel compression was associated with decreased shear stress and increased blood residence time.     

Potential of stem cell-derived exosomes to regenerate β islets through Pdx-1 dependent mechanism in a rat model of type 1 diabetes

Type 1 diabetes, has been recognized as an autoimmune disease. Like other immunological conditions, regulation of immune response is a key strategy to control the autoimmunity in diabetic patients. Mesenchymal stem cells have been shown to have a distinct potential in modulating the immune reactions. However, treatment with stem cells is combined with concerns about safety issues. To overcome these concerns, in this study, we have utilized the regenerative potential of exosomes isolated from menstrual blood-derived mesenchymal stem cells to restore the β-cell mass and insulin production in type 1 diabetes. Exosomes are nanovesicles containing various cargos involved in cellular communications. Streptozotocin was used to induce islet destruction and diabetes in male Wistar rats. Then, exosomes were intravenously injected into animals at different time points and in a single or repeated therapeutic doses. After about 6 weeks, animals were euthanized and the pancreas was analyzed for the presence of the regenerated β islets as well as the insulin secretion. The non-fasting blood glucose and the serum insulin level were also monitored during the study. Our results represented that menstrual blood-derived mesenchymal stem cell-derived exosomes enhance the β-cell mass and insulin production in the pancreas of diabetic animals that received repeated doses of exosomes. Immunohistochemistry analysis also confirmed the presence of insulin in the islets of treated animals. Further investigations proposed that exosomes induce the islet regeneration through pancreatic and duodenal homeobox 1 pathway. The exosome tracking also revealed the homing of injected exosomes to the pancreas.     

Epigenetic-based therapy for colorectal cancer: Prospect and involved mechanisms

Epigenetic modifications are heritable variations in gene expression not encoded by the DNA sequence. According to reports, a large number of studies have been performed to characterize epigenetic modification during normal development and also in cancer. Epigenetics can be regarded more widely to contain all of the changes in expression of genes that make by adjusted interactions between the regulatory portions of DNA or messenger RNAs that lead to indirect variation in the DNA sequence. In the last decade, epigenetic modification importance in colorectal cancer (CRC) pathogenesis was demonstrated powerfully. Although developments in CRC therapy have been made in the last years, much work is required as it remains the second leading cause of cancer death. Nowadays, epigenetic programs and genetic change have pivotal roles in the CRC incidence as well as progression. While our knowledge about epigenetic mechanism in CRC is not comprehensive, selective histone modifications and resultant chromatin conformation together with DNA methylation most likely regulate CRC pathogenesis that involved genes expression. Undoubtedly, the advanced understanding of epigenetic-based gene expression regulation in the CRC is essential to make epigenetic drugs for CRC therapy. The major aim of this review is to deliver a summary of valuable results that represent evidence of principle for epigenetic-based therapeutic approaches employment in CRC with a focus on the advantages of epigenetic-based therapy in the inhibition of the CRC metastasis and proliferation.     

Masculinization of the gynogenetic juvenile ship sturgeon (Acipenser nudiventris Lovetsky, 1828) using 17α‐methyl testosterone

In sturgeons, the induction of gynogenesis and sex reversal could be important for potential production of neomale sturgeon and all‐female progeny for caviar production. The aim of this study was sex reversal of ship sturgeon (Acipenser nudiventris Lovetsky, 1828) gynogen into male sex. Five‐month‐old gynogens were sex reversed into male by including 17α‐methyl testosterone in their food for 7 months. Three treatments were considered as follows: (a) without treated (gynogen control), (b) 10 mg MT/kg diet, and (c) 50 mg MT/kg diet. All treatments (60 individuals) were sampled both the 30 and 36 months old and their sex was determined using classical histology method of gonad. The sex ratio of the progenies in the gynogen control were 73.3% female and 26.7% male. In treatment of 10 mg MT/kg feed, 18 specimens were studied that half of them (50%) showed pseudo‐testicular structure in the female gonad. That is 50% of the specimens were intersex, 27.7% were male and 22.3% were female. All of the fish fed by 50 mg MT/kg feed had been sex reversed to male. Sexual maturation of these fish had been recognized in stage III at 36 months old. In conclusion, 50 mg MT/kg feed found as effective dose for successful sex reversal in gynogenetic ship sturgeon.