4-(3-Alkyl/benzyl-guanidino)benzenesulfonamides as selective carbonic anhydrase VII inhibitors

The treatment of chronic neuropathic pain remains one of the most challenging of all neurological diseases and very much an art. There exists no consensus for the optimal management of this condition at the moment. Gaining inspiration from recent studies which pointed out the involvement of brain-associated carbonic anhydrase (CA, EC 4.2.1.1) isoform VII in the pathology of various neurodegenerative diseases, which highlighted the relationship between selective inhibition of this isozyme and relieve of neuropathic pain, herein we report the synthesis and CA VII inhibitory activity of novel 4-(3-alkyl/benzyl-guanidino)benzenesulfonamides. Ten benzyl-substituted and five alkyl-substituted 4-guanidinobenzenesulfonamide derivatives were obtained, some of which (7c, 7h, 7m and 7o) exhibited satisfactory selectivity towards CA VII over CA I and II, with K_I-s in the subnanomolar range and good selectivity indexes for inhibiting the target versus the off-target isoforms.     

Oxidative stress‐induced renal telomere shortening as a mechanism of cyclosporine‐induced nephrotoxicity

Due to the association of oxidative stress and telomere shortening, it was aimed in the present study to investigate the possibility whether cyclosporine‐A exerts its nephrotoxic side effects via induction of oxidative stress‐induced renal telomere shortening and senescent phenotype in renal tissues of rats. Renal oxidative stress markers, 8‐hydroxydeoxyguanosine, malondialdehyde, and protein carbonyl groups were measured by standard methods. Telomere length and telomerase activity were also evaluated in kidney tissue samples. Results showed that cyclosporine‐A treatment significantly (P < 0.05) enhanced renal malondialdehyde, 8‐hydroxydeoxyguanosine, and protein carbonyl groups levels, decreased renal telomere length, and deteriorated renal function compared with the controls. Renal telomerase activity was not affected by cyclosporine‐A. Renal telomere length could be considered as an important parameter of both oxidative stress and kidney function. Telomere shortening and accelerated kidney aging may be caused by cyclosporine‐induced oxidative stress, indicating the potential mechanism of cyclosporine‐induced nephrotoxicity.     

Isolation and characterization of ACC deaminase-producing fluorescent pseudomonads, to alleviate salinity stress on canola (Brassica napus L.) growth

Salinity stress is of great importance in arid and semi-arid areas of the world due to its impact in reducing crop yield. Under salinity stress, the amount of 1-aminocyclopropane-1-carboxylate (ACC), a precursor for ethylene production in plants, increases. Here, we conducted research under the hypothesis that isolated ACC deaminase-producing Pseudomonas fluorescens and Pseudomonas putida can alleviate the stressful effects of salinity on canola (Brassica napus L.) growth. The experiments were conducted in the Soil and Water Research Institute, Tehran, Iran. Seven experimental stages were conducted to isolate and characterize ACC deaminase-producing Pseudomonas fluorescens strains and to determine factors enhancing their growth and, consequently, their effects on the germination of canola seeds. Under salinity stress, in 14% of the isolates, ACC deaminase activity was observed, indicating that they were able to utilize ACC as the sole N-source. Bacterial strains differed in their ability to synthesize auxin and hydrogen cyanide compounds, as well as in their ACC deaminase activity. Under salinity stress, the rate of germinating seeds inoculated with the strains of ACC deaminase-producing Pseudomonas fluorescens and Pseudomonas putida, and seedling growth was significantly higher. These results indicate the significance of soil biological activities, including the activities of plant growth-promoting bacteria, in the alleviation of soil stresses such as salinity on plant growth.     

Plant–Microbe Symbiosis: What Has Proteomics Taught Us?

Beneficial microbes have a positive impact on the productivity and fitness of the host plant. A better understanding of the biological impacts and underlying mechanisms by which the host derives these benefits will help to address concerns around global food production and security. The recent development of omics‐based technologies has broadened our understanding of the molecular aspects of beneficial plant–microbe symbiosis. Specifically, proteomics has led to the identification and characterization of several novel symbiosis‐specific and symbiosis‐related proteins and post‐translational modifications that play a critical role in mediating symbiotic plant–microbe interactions and have helped assess the underlying molecular aspects of the symbiotic relationship. Integration of proteomic data with other “omics” data can provide valuable information to assess hypotheses regarding the underlying mechanism of symbiosis and help define the factors affecting the outcome of symbiosis. Herein, an update is provided on the current and potential applications of symbiosis‐based “omic” approaches to dissect different aspects of symbiotic plant interactions. The application of proteomics, metaproteomics, and secretomics as enabling approaches for the functional analysis of plant‐associated microbial communities is also discussed.     

Risk of coronary artery stenosis in Iranian type 2 diabetics: is there a role for matrix metalloproteinase-3 gene (-1612 5A/6A) polymorphism?

Aim  

To investigate the association of matrix metalloproteinase-3 (MMP-3) polymorphism with susceptibility to coronary artery stenosis (CAS) and the number of diseased vessels in patients with type 2 diabetes mellitus (T2DM).     

In silico and in vitro effects of the I30T mutation on myelin protein zero instability in the cell membrane

Charcot‐Marie‐Tooth (CMT) diseases are a heterogeneous group of genetic peripheral neuropathies caused by mutations in a variety of genes, which are involved in the development and maintenance of peripheral nerves. Myelin protein zero (MPZ) is expressed by Schwann cells, and MPZ mutations can lead to primarily demyelinating polyneuropathies including CMT type 1B. Different mutations demonstrate various forms of disease pathomechanisms, which may be beneficial in understanding the disease cellular pathology. Our molecular dynamics simulation study on the possible impacts of I30T mutation on the MPZ protein structure suggested a higher hydrophobicity and thus lower stability in the membranous structures. A study was also conducted to predict native/mutant MPZ interactions. To validate the results of the simulation study, the native and mutant forms of the MPZ protein were separately expressed in a cellular model, and the protein trafficking was chased down in a time course pattern. In vitro studies provided more evidence on the instability of the MPZ protein due to the mutation. In this study, qualitative and quantitative approaches were adopted to confirm the instability of mutant MPZ in cellular membranes.     

Computationally Design of Inhibitory Peptides Against Wnt Signaling Pathway: In Silico Insight on Complex of DKK1 and LRP6

Wnt signaling pathway plays a major role in the regulation of cell proliferation, migration, tissue homeostasis, tumor progression and cancer. This pathway can be antagonized by different proteins such as DKK proteins, which disrupt the initiatory complex (Frizzled–LRP6 complex). Therefore, interruption of its formation could be a promising strategy for the design of Low-density lipoprotein receptor-Related Protein 6 (LRP6) inhibitors. A computational study was conducted in order to assist in the design of inhibitory peptides against LRP6 as co-receptor of frizzled. Twelve fragments as peptide derivatives of natural ligand of LRP6 receptor (DKK1) were designed using the information from the analysis of the DKK1_C/LRP6 complex, hot spot residues and the secondary structure. These fragments were based on cys2 domain of DKK1. The designed peptides were energy minimized by molecular dynamics simulations in the presence and absence of LRP6 receptor and their binding affinities were investigated via molecular docking using ClusPro, HADDOCK and PRODIGY webservers. Finally, the stability and free energy of binding in peptides were calculated by FoldX software. The results showed that four designed peptides had the highest affinity (the interaction energy: ?10.2867, ?10.1388, ?7.94339 and ?7.57536 kcal/mol) to interact with the receptor which showed the most interacting residues and the lowest free energy of binding. Also, the RMSD, RMSF and RoG of the protein–peptide complex exhibited less structural fluctuations which can be linked to the stability of peptides associated to the receptor. These peptides may be considered as candidates for inhibiting Wnt signaling pathway through LRP6 receptor.     

Deep Subwavelength Confinement of Mid-infrared Plasmon Modes by Coupling Graphene-Coated Nanowire with a Dielectric Substrate

In this paper, we report the realization of highly confined mid-infrared plasmon modes by coupling freestanding graphene-coated nanowire with a dielectric substrate. It is shown that the presence of a nearby dielectric substrate not only breaks the azimuthal symmetry of the plasmon modes but also has a strong impact on the coupling and hybridization of these modes. The degree of interactions with the substrate depends on the permittivity of the substrate, the key structural parameters of the nanowire, the operation frequency and chemical potential of graphene, as well as the gap distance between the nanowire and supporting substrate. It is found that compared to freestanding case, using a high-index substrate and adjusting the gap distance can result in the following benefits: (i) an ultra-small mode area and a long propagation length can be realized simultaneously, (ii) a stronger field enhancement in the low-index gap region and improved figure of merit can be achieved, and (iii) a huge reduction in the crosstalk can be made which is crucial for the realization of high-density integrated nanophotonic devices.