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.     

Design and synthesis of novel 3,5-bis-N-(aryl/heteroaryl) carbamoyl-4-aryl-1,4-dihydropyridines as small molecule BACE-1 inhibitors

Alzheimer disease (AD) is a neuronal dementia for which no treatment has been consolidated yet. Major pathologic hallmark of AD is the aggregated extracellular amyloid-β plaques in the brains of disease sufferers. Aβ-peptide is a major component of amyloid plaques and is produced from amyloid precursor protein (APP) via the proteolysis action. An aspartyl protease known as β-site amyloid precursor protein cleaving enzyme (BACE-1) is responsible for this proteolytic action. Distinctive role of BACE-1 in AD pathogenesis has made it a validated target to develop anti-Alzheimer agents. Our structure-based virtual screening method led to the synthesis of novel 3,5-bis-N-(aryl/heteroaryl) carbamoyl-4-aryl-1,4-dihydropyridine BACE-1 inhibitors (6a–6p; in vitro hits). Molecular docking and DFT-based ab initio studies using B3LYP functional in association with triple-ζ basis set (TZV) proposed binding mode and binding energies of ligands in the active site of the receptor. In vitro BACE-1 inhibitory activities were determined by enzymatic fluorescence resonance energy transfer (FRET) assay. Most of the synthesized dihydropyridine scaffolds were active against BACE-1 while 6d, 6k, 6n and 6a were found to be the most potent molecules with IC₅₀ values of 4.21, 4.27, 4.66 and 6.78 μM, respectively. Superior BACE-1 inhibitory activities were observed for dihydropyridine derivatives containing fused/nonfused thiazole containing groups, possibly attributing to the additional interactions with S2–S3 subpocket residues. Relatively reliable correlation between calculated binding energies and experimental BACE-1 inhibitory activities was achieved (R² = 0.51). Moreover, compounds 6d, 6k, 6n and 6a exhibited relatively no calcium channel blocking activity with regard to nifedipine suggesting them as appropriate candidates for further modification(s) to BACE-1 inhibitory scaffolds.     

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.     

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.     

RIC-8 is required for GPR-1/2-dependent Galpha function during asymmetric division of C. elegans embryos

Heterotrimeric G proteins are crucial for asymmetric cell division, but the mechanisms of signal activation remain poorly understood. Here, we establish that the evolutionarily conserved protein RIC-8 is required for proper asymmetric division of one-cell stage C. elegans embryos. Spindle severing experiments demonstrate that RIC-8 is required for generation of substantial pulling forces on astral microtubules. RIC-8 physically interacts with GOA-1 and GPA-16, two Galpha subunits that act in a partially redundant manner in one-cell stage embryos. RIC-8 preferentially binds to GDP bound GOA-1 and is a guanine nucleotide exchange factor (GEF) for GOA-1. Our analysis suggests that RIC-8 acts before the GoLoco protein GPR-1/2 in the sequence of events leading to Galpha activation. Furthermore, coimmunoprecipitation and in vivo epistasis demonstrate that inactivation of the Gbeta subunit GPB-1 alleviates the need for RIC-8 in one-cell stage embryos. Our findings suggest a mechanism in which RIC-8 favors generation of Galpha free from Gbetagamma and enables GPR-1/2 to mediate asymmetric cell division.