The involvement of protein kinase G inhibitor in regulation of apoptosis and autophagy markers in spatial memory deficit induced by Aβ

The role of nitric oxide/protein kinase G (NO/PKG) in neurodegenerative disorders is controversial in different circumstances. PKG affects neurons both by itself and as a result of increased NO concentration. In this study, we examined the influence of PKG on spatial memory by intrahippocampal administration of three different concentrations of KT5823 as a PKG inhibitor. Morris water maze (MWM) was used for evaluation of behavioral alterations. We also measured the apoptosis and autophagy markers as two probable interfering pathways with PKG signaling by Western blot method. We found that in Aβ‐pretreated rats, intrahippocampus infusions of 2.5, 5, and 10 μm /side of KT5823 led to a significant reduction in escape latency and traveled distance comparing to Aβ‐treatment group. Our molecular findings indicated that KT5823 could induce autophagy and attenuate apoptotic markers at distinct doses. Here, we can conclude that in addition to other parameters, apoptosis, and autophagy in part have damaging and protective roles, respectively, in PKG signaling mechanisms. As autophagy‐related proteins lose their functions in neurodegenerative diseases, we can suggest that autophagy can be one of the therapeutic aims for remedy of Alzheimer's disease.     

Is the CCR5 Δ 32 Mutation Associated with Immune System-Related Diseases?

Hypersensitivity and autoimmunity are the main features of immune system-related diseases such as type 2 diabetes (T2D), multiple sclerosis (MS), and asthma. It has been established that chemokines play key roles in the activation and regulation of immune cell migration which is important in the pathogenesis of the diseases mentioned. CC chemokines receptor 5 or CCR5 is a receptor for RANTES, MIP-1α, and MIP-1β and is expressed by several immune cells including NK cells, T lymphocytes, and macrophages. It plays key roles in the regulation of migration and activation of the immune cells during immune responses against microbe and self-antigens during autoimmunity and hypersensitivity disorders. Therefore, any alteration in the sequence of CCR5 gene or in its expression could be associated with immune system-related diseases. Previous studies revealed that a 32-base pair deletion (Δ 32) in exon 1 of the CCR5 gene led to downregulation of the gene. Previous studies demonstrated that not only CCR5 expression was altered in autoimmune and hypersensitivity disorders, but also that the mutation is associated with the diseases. This review addresses the recent information regarding the association of the CCR5 Δ 32 mutation in immune-related diseases including T2D with and without nephropathy, MS, and asthma. Based on the collected data, it seems that the CCR5 Δ 32 mutation can be considered as a risk factor for MS, but not asthma and T2D with and without nephropathy.     

Cannabinoid CB1 receptors of the rat central amygdala mediate anxiety-like behavior: interaction with the opioid system

Cannabinoids, which are the active compounds of marijuana, produce some pharmacological effects similar to the opioids. In addition, there are functional interactions between the cannabinoid and opioid systems. In this study, we investigated the effects of intraperitoneal (i.p.) injection of opioid drugs on responses induced by intracentral amygdala (intra-CeA) microinjection of cannabinoid CB1 receptor agents in rats, using the elevated plus maze test of anxiety. I.p. injection of morphine (6 and 9 mg/kg) 30 min before testing, increased the percentage open arm time (%OAT) and the percentage open arm entries (%OAE), but not locomotor activity, showing an anxiolytic-like response. I.p. administration of the opioid receptor antagonist, naloxone (1 mg/kg) 15 min before testing, significantly reduced %OAT, but not %OAE and locomotor activity. The drug, however, tended to decrease locomotor activity. Intra-CeA administration of arachidonylcyclopropylamide (ACPA, an agonist shown to selectively activate CB1 receptors; 1.25 and 5 ng/rat) increased %OAT and %OAE but not locomotor activity, indicating an anxiolytic-like response. Coadministration of morphine (6 mg/kg, i.p.) plus ACPA (0.125 ng/rat, intra-CeA) increased the anxiolytic-like response. Administration of naloxone reversed the effects of intra-CeA injection of ACPA. Intra-CeA administration of the cannabinoid CB1 receptor antagonist, AM251 (2.5, 25, and 100 ng/rat) did not alter %OAT and %OAE, but the higher doses of the drug (25 and 100 ng/rat) reduced locomotor activity. Coadministration of morphine (6 mg/kg) or naloxone (0.1 mg/kg) with AM251 showed an anxiolytic-like response. In conclusion, the results may indicate an anxiolytic-like effect for cannabinoid CB1 receptors of the CeA and the existence of an interaction between the cannabinoid and the opioid systems in the modulation of anxiety.     

GB Virus C/Hepatitis G Virus Envelope Glycoprotein E2: Computational Molecular Features and Immunoinformatics Study

Introduction:

GB virus C (GBV-C) or hepatitis G virus (HGV) is an enveloped, RNA positive-stranded flavivirus-like particle. E2 envelope protein of GBV-C plays an important role in virus entry into the cytosol, genotyping and as a marker for diagnosing GBV-C infections. Also, there is discussion on relations between E2 protein and gp41 protein of HIV. The purposes of our study are to multi aspect molecular evaluation of GB virus C E2 protein from its characteristics, mutations, structures and antigenicity which would help to new directions for future researches.

Evidence Acquisition:

Briefly, steps followed here were; retrieving reference sequences of E2 protein, entropy plot evaluation for finding the mutational /conservative regions, analyzing potential Glycosylation, Phosphorylation and Palmitoylation sites, prediction of primary, secondary and tertiary structures, then amino acid distributions and transmembrane topology, prediction of T and B cell epitopes, and finally visualization of epitopes and variations regions in 3D structure.

Results:

Based on the entropy plot, 3 hypervariable regions (HVR) observed along E2 protein located in residues 133-135, 256-260 and 279-281. Analyzing primary structure of protein sequence revealed basic nature, instability, and low hydrophilicity of this protein. Transmembrane topology prediction showed that residues 257-270 presented outside, while residues 234- 256 and 271-293 were transmembrane regions. Just one N-glycosylation site, 5 potential phosphorylated peptides and two palmitoylation were found. Secondary structure revealed that this protein has 6 α-helix, 12 β-strand 17 Coil structures. Prediction of T-cell epitopes based on HLA-A*02:01 showed that epitope NH3-LLLDFVFVL-COOH is the best antigen icepitope. Comparative analysis for consensus B-cell epitopes regarding transmembrane topology, based on physico-chemical and machine learning approaches revealed that residue 231- 296 (NH2- EARLVPLILLLLWWWVNQLAVLGLPAVEAAVAGEVFAGPALSWCLGLPVVSMILGLANLVLYFRWL-COOH) is most effective and probable B cell epitope for E2 protein.

Conclusions:

The comprehensive analysis of a protein with important roles has never been easy, and in case of E2 envelope glycoprotein of HGV, there is no much data on its molecular and immunological features, clinical significance and its pathogenic potential in hepatitis or any other GBV-C related diseases. So, results of the present study may explain some structural, physiological and immunological functions of this protein in GBV-C, as well as designing new diagnostic kits and besides, help to better understandingE2 protein characteristic and other members of Flavivirus family, especially HCV.     

Radioiodination and preclinical evaluation of 4-benzyl-1-(3-[<Superscript>125</Superscript>I]-iodobenzylsulfonyl)piperidine as a breast tumor imaging tracer in mouse

Objective

4-Benzyl-1-(3-iodobenzylsulfonyl)piperidine, 4-B-IBSP, has shown high-binding affinity to both sigma (σ) receptors in our previous work. In current study, radiolabeling and preclinical evaluation of 4-benzyl-1-(3-[¹²⁵I]-iodobenzylsulfonyl)piperidine, 4-B-[¹²⁵I]IBSP, in human ductal breast carcinoma (T47D) cells and in breast adenocarcinoma-bearing BALB/c mice are described.

Methods

Radioiodination of this new σ ligand was performed by a palladium-catalyzed stannylation approach followed by oxidative iododestannylation reaction using Iodo-Gen. Competition-binding assays for binding of 4-B-[¹²⁵I]IBSP to guinea pig brain membranes and to T47D cells were performed with known σ ligands. The selectivity and binding characteristics (B _max and K _d) were analyzed. In vitro stability and in vivo blood metabolism studies were also evaluated. Moreover, biodistribution studies were performed in normal and into the tumor-bearing mice at interval time points post-injection (p.i.). Both in vitro and in vivo blockade experiments were done in the presence of the σ receptors blocking agents.

Results

Radioiodinated ligand was obtained in high yield and high specific activity. The σ inhibition constants (K _i, nM) for 4-(3-iodobenzyl)-1-(benzylsulfonyl)piperazine (4-IBBSPz), (+)-pentazocine, haloperidol, DTG, and 4-B-IBSP were 1.37?±?0.19, 3.90?±?0.77, 2.69?±?0.33, 30.62?±?2.01, and 0.61?±?0.05, respectively. 4-B-[¹²⁵I]IBSP bound to σ receptor sites preferably to very high-affinity binding sites on T47D cells. The radioligand showed acceptable in vitro and in vivo stabilities in the blood pool. However, in vivo biodistribution studies in normal Swiss albino mice revealed fast clearance of 4-B-[¹²⁵I]IBSP from blood and the other normal organs. Biodistribution experiments of 4-B-[¹²⁵I]IBSP in breast adenocarcinoma tumor-bearing BALB/c mice showed a relatively high tumor uptake at 30 min p.i. (4.13?±?0.95) that reaches to 1.57?±?0.24 even after 240 min p.i. A pre-injection of 4-B-IBSP and haloperidol with 4-B-[¹²⁵I]IBSP resulted in 36–57% decrease in activity in the tumor, liver, and brain at 60 min p.i.

Conclusions

The high affinity of 4-B-[¹²⁵I]IBSP to σ receptor-binding sites, its relatively high uptake, and preferential retention in the tumor as well as an increasing trend observed in the tumor to blood and in the tumor to muscle ratios suggests that an iodine-123 labeled counterpart, 4-B-[¹²³I]IBSP, would be a promising σ radioligand for pursuing further studies to assess its potential for breast tumors imaging with SPECT.

     

Correction: Green synthesis of Pd nanoparticles supported on reduced graphene oxide,using the extract of Rosa canina fruit,and their use as recyclable and heterogeneous nanocatalysts for the degradation of dye pollutants in water

Correction for ‘Correction: Green synthesis of Pd nanoparticles supported on reduced graphene oxide, using the extract of Rosa canina fruit, and their use as recyclable and heterogeneous nanocatalysts for the degradation of dye pollutants in water’ by Saba Hemmati et al., RSC Adv., 2018, 8, 22763–22763.

The affiliations in the original article were transposed; the corrected affiliations are as shown below.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

Needs assessment of dual diagnosis: A cross-sectional survey using routine clinical data

Aims: Department of Health guidance on dual diagnosis (DD) recommends that services measure local need, and use this to inform service planning. This study aimed to use routine clinical data to estimate the prevalence of DD and unmet treatment need in a community drug and alcohol service, and to appraise the feasibility of using routine data for such purposes.

Methods: First, a screening checklist was developed to determine whether a particular service-user met DD caseness criteria. Second, the electronic care records of 227 service-users were screened for DD caseness, as well as for documentation of current and/or previous receipt of mental health treatment.

Findings: Seventy-two percent screened positive for having DD. Of these, around half were not receiving current treatment for their mental health, while 37% had never received mental health treatment. Higher rates of DD were found amongst women and those in treatment for alcohol dependence.

Conclusions: The findings corroborate previous research showing high prevalences of DD and unmet treatment need within drug and alcohol services in general, and amongst certain high-risk subgroups in particular. The study demonstrates that using routine data to estimate unmet treatment need is feasible within the limited resources available to frontline services.