Next Issue
Previous Issue

E-Mail Alert

Add your e-mail address to receive forthcoming issues of this journal:

Journal Browser

Journal Browser

Table of Contents

Int. J. Mol. Sci., Volume 19, Issue 2 (February 2018)

  • Issues are regarded as officially published after their release is announced to the table of contents alert mailing list.
  • You may sign up for e-mail alerts to receive table of contents of newly released issues.
  • PDF is the official format for papers published in both, html and pdf forms. To view the papers in pdf format, click on the "PDF Full-text" link, and use the free Adobe Readerexternal link to open them.
Cover Story (view full-size image) The IL-23/IL-17 axis mediates the initiation and persistence of inflammation during Psoriasis and [...] Read more.
View options order results:
result details:
Displaying articles 1-327
Export citation of selected articles as:
Open AccessArticle Fine Physical Bin Mapping of the Powdery Mildew Resistance Gene Pm21 Based on Chromosomal Structural Variations in Wheat
Int. J. Mol. Sci. 2018, 19(2), 643; https://doi.org/10.3390/ijms19020643
Received: 31 January 2018 / Revised: 19 February 2018 / Accepted: 22 February 2018 / Published: 24 February 2018
PDF Full-text (342 KB) | HTML Full-text | XML Full-text
Abstract
Pm21, derived from wheat wild relative Dasypyrum villosum, is one of the most effective powdery mildew resistance genes and has been widely applied in wheat breeding in China. Mapping and cloning Pm21 are of importance for understanding its resistance mechanism. In
[...] Read more.
Pm21, derived from wheat wild relative Dasypyrum villosum, is one of the most effective powdery mildew resistance genes and has been widely applied in wheat breeding in China. Mapping and cloning Pm21 are of importance for understanding its resistance mechanism. In the present study, physical mapping was performed using different genetic stocks involving in structural variations of chromosome 6VS carrying Pm21. The data showed that 6VS could be divided into eight distinguishable chromosomal bins, and Pm21 was mapped to the bin FLb4–b5/b6 closely flanked by the markers 6VS-08.6 and 6VS-10.2. Comparative genomic mapping indicated that the orthologous regions of FLb4–b5/b6 carrying Pm21 were narrowed to a 117.7 kb genomic region harboring 19 genes in Brachypodium and a 37.7 kb region harboring 5 genes in rice, respectively. The result was consistent with that given by recent genetic mapping in diploid D. villosum. In conclusion, this study demonstrated that physical mapping based on chromosomal structural variations is an efficient method for locating alien genes in wheat background. Full article
(This article belongs to the Section Molecular Plant Sciences)
Figures

Graphical abstract

Open AccessArticle Refining the Results of a Classical SELEX Experiment by Expanding the Sequence Data Set of an Aptamer Pool Selected for Protein A
Int. J. Mol. Sci. 2018, 19(2), 642; https://doi.org/10.3390/ijms19020642
Received: 9 January 2018 / Revised: 9 February 2018 / Accepted: 19 February 2018 / Published: 24 February 2018
PDF Full-text (3337 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
New, as yet undiscovered aptamers for Protein A were identified by applying next generation sequencing (NGS) to a previously selected aptamer pool. This pool was obtained in a classical SELEX (Systematic Evolution of Ligands by EXponential enrichment) experiment using the FluMag-SELEX procedure followed
[...] Read more.
New, as yet undiscovered aptamers for Protein A were identified by applying next generation sequencing (NGS) to a previously selected aptamer pool. This pool was obtained in a classical SELEX (Systematic Evolution of Ligands by EXponential enrichment) experiment using the FluMag-SELEX procedure followed by cloning and Sanger sequencing. PA#2/8 was identified as the only Protein A-binding aptamer from the Sanger sequence pool, and was shown to be able to bind intact cells of Staphylococcus aureus. In this study, we show the extension of the SELEX results by re-sequencing of the same aptamer pool using a medium throughput NGS approach and data analysis. Both data pools were compared. They confirm the selection of a highly complex and heterogeneous oligonucleotide pool and show consistently a high content of orphans as well as a similar relative frequency of certain sequence groups. But in contrast to the Sanger data pool, the NGS pool was clearly dominated by one sequence group containing the known Protein A-binding aptamer PA#2/8 as the most frequent sequence in this group. In addition, we found two new sequence groups in the NGS pool represented by PA-C10 and PA-C8, respectively, which also have high specificity for Protein A. Comparative affinity studies reveal differences between the aptamers and confirm that PA#2/8 remains the most potent sequence within the selected aptamer pool reaching affinities in the low nanomolar range of KD = 20 ± 1 nM. Full article
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
Figures

Graphical abstract

Open AccessReview Plant Mitochondrial Inner Membrane Protein Insertion
Int. J. Mol. Sci. 2018, 19(2), 641; https://doi.org/10.3390/ijms19020641
Received: 2 February 2018 / Revised: 20 February 2018 / Accepted: 22 February 2018 / Published: 24 February 2018
Cited by 1 | PDF Full-text (776 KB) | HTML Full-text | XML Full-text
Abstract
During the biogenesis of the mitochondrial inner membrane, most nuclear-encoded inner membrane proteins are laterally released into the membrane by the TIM23 and the TIM22 machinery during their import into mitochondria. A subset of nuclear-encoded mitochondrial inner membrane proteins and all the mitochondrial-encoded
[...] Read more.
During the biogenesis of the mitochondrial inner membrane, most nuclear-encoded inner membrane proteins are laterally released into the membrane by the TIM23 and the TIM22 machinery during their import into mitochondria. A subset of nuclear-encoded mitochondrial inner membrane proteins and all the mitochondrial-encoded inner membrane proteins use the Oxa machinery—which is evolutionarily conserved from the endosymbiotic bacterial ancestor of mitochondria—for membrane insertion. Compared to the mitochondria from other eukaryotes, plant mitochondria have several unique features, such as a larger genome and a branched electron transport pathway, and are also involved in additional cellular functions such as photorespiration and stress perception. This review focuses on the unique aspects of plant mitochondrial inner membrane protein insertion machinery, which differs from that in yeast and humans, and includes a case study on the biogenesis of Cox2 in yeast, humans, two plant species, and an algal species to highlight lineage-specific similarities and differences. Interestingly, unlike mitochondria of other eukaryotes but similar to bacteria and chloroplasts, plant mitochondria appear to use the Tat machinery for membrane insertion of the Rieske Fe/S protein. Full article
(This article belongs to the Special Issue Plant Mitochondria)
Figures

Figure 1

Open AccessArticle Non-Native Conformational Isomers of the Catalytic Domain of PCSK9 Induce an Immune Response, Reduce Lipids and Increase LDL Receptor Levels
Int. J. Mol. Sci. 2018, 19(2), 640; https://doi.org/10.3390/ijms19020640
Received: 11 January 2018 / Revised: 16 February 2018 / Accepted: 19 February 2018 / Published: 24 February 2018
PDF Full-text (3383 KB) | HTML Full-text | XML Full-text
Abstract
PCSK9 (Proprotein convertase subtilisin/kexin type 9) increases plasma cholesterol levels by promoting LDL receptor degradation. Current antibody inhibitors block the interaction between PCSK9 and LDL receptors, significantly decrease plasma cholesterol levels, and provide beneficial clinical outcomes. To reduce the action of PCSK9 in
[...] Read more.
PCSK9 (Proprotein convertase subtilisin/kexin type 9) increases plasma cholesterol levels by promoting LDL receptor degradation. Current antibody inhibitors block the interaction between PCSK9 and LDL receptors, significantly decrease plasma cholesterol levels, and provide beneficial clinical outcomes. To reduce the action of PCSK9 in plasma, a novel strategy that will produce a panel of non-native, conformationally-altered isomers of PCSK9 (X-PCSK9) to develop active immunotherapy targeting of native PCSK9 and inhibiting/blocking the interaction of PCSK9 with LDL receptor, thus decreasing plasma cholesterol levels is proposed. The authors used the scrambled disulfide bond technique to generate conformationally-altered isomers of the catalytic domain of mouse PCSK9. The focus was on the immune response of four X-isomers and their effects on plasma cholesterol and triglyceride levels in both C57BL/6J and Apoe−/− mice. The authors showed that the four immunogens produced significant immunogenicity against native PCSK9 to day 120 after immunization of C57BL/6J and Apoe−/− mice. This resulted in significantly decreased plasma cholesterol levels in C57BL/6J mice, and to a lesser degree in Apoe−/− mice. The X-PCSK9-B1 treated mice had increased LDL receptor mRNA and protein levels at day 120 after treatment. Thus, this study provides a new, potentially promising approach that uses long-term immunotherapy for a treatment of hypercholesterolemia. Full article
(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism)
Figures

Figure 1a

Open AccessReview Ten Prominent Host Proteases in Plant-Pathogen Interactions
Int. J. Mol. Sci. 2018, 19(2), 639; https://doi.org/10.3390/ijms19020639
Received: 2 February 2018 / Revised: 17 February 2018 / Accepted: 17 February 2018 / Published: 24 February 2018
Cited by 1 | PDF Full-text (677 KB) | HTML Full-text | XML Full-text
Abstract
Proteases are enzymes integral to the plant immune system. Multiple aspects of defence are regulated by proteases, including the hypersensitive response, pathogen recognition, priming and peptide hormone release. These processes are regulated by unrelated proteases residing at different subcellular locations. In this review,
[...] Read more.
Proteases are enzymes integral to the plant immune system. Multiple aspects of defence are regulated by proteases, including the hypersensitive response, pathogen recognition, priming and peptide hormone release. These processes are regulated by unrelated proteases residing at different subcellular locations. In this review, we discuss 10 prominent plant proteases contributing to the plant immune system, highlighting the diversity of roles they perform in plant defence. Full article
(This article belongs to the Special Issue Plant Defense Genes Against Biotic Stresses)
Figures

Graphical abstract

Open AccessArticle Arabidopsis RETICULON-LIKE3 (RTNLB3) and RTNLB8 Participate in Agrobacterium-Mediated Plant Transformation
Int. J. Mol. Sci. 2018, 19(2), 638; https://doi.org/10.3390/ijms19020638
Received: 31 January 2018 / Revised: 21 February 2018 / Accepted: 21 February 2018 / Published: 24 February 2018
PDF Full-text (2903 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Agrobacterium tumefaciens can genetically transform various eukaryotic cells because of the presence of a resident tumor-inducing (Ti) plasmid. During infection, a defined region of the Ti plasmid, transfer DNA (T-DNA), is transferred from bacteria into plant cells and causes plant cells to abnormally
[...] Read more.
Agrobacterium tumefaciens can genetically transform various eukaryotic cells because of the presence of a resident tumor-inducing (Ti) plasmid. During infection, a defined region of the Ti plasmid, transfer DNA (T-DNA), is transferred from bacteria into plant cells and causes plant cells to abnormally synthesize auxin and cytokinin, which results in crown gall disease. T-DNA and several virulence (Vir) proteins are secreted through a type IV secretion system (T4SS) composed of T-pilus and a transmembrane protein complex. Three members of Arabidopsis reticulon-like B (RTNLB) proteins, RTNLB1, 2, and 4, interact with VirB2, the major component of T-pilus. Here, we have identified that other RTNLB proteins, RTNLB3 and 8, interact with VirB2 in vitro. Root-based A. tumefaciens transformation assays with Arabidopsis rtnlb3, or rtnlb5-10 single mutants showed that the rtnlb8 mutant was resistant to A. tumefaciens infection. In addition, rtnlb3 and rtnlb8 mutants showed reduced transient transformation efficiency in seedlings. RTNLB3- or 8 overexpression transgenic plants showed increased susceptibility to A. tumefaciens and Pseudomonas syringae infection. RTNLB1-4 and 8 transcript levels differed in roots, rosette leaves, cauline leaves, inflorescence, flowers, and siliques of wild-type plants. Taken together, RTNLB3 and 8 may participate in A. tumefaciens infection but may have different roles in plants. Full article
(This article belongs to the Special Issue Plant Innate Immunity 2.0)
Figures

Graphical abstract

Open AccessArticle Phosphate-Catalyzed Succinimide Formation from Asp Residues: A Computational Study of the Mechanism
Int. J. Mol. Sci. 2018, 19(2), 637; https://doi.org/10.3390/ijms19020637
Received: 6 February 2018 / Revised: 22 February 2018 / Accepted: 22 February 2018 / Published: 24 February 2018
PDF Full-text (2811 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Aspartic acid (Asp) residues in proteins and peptides are prone to the non-enzymatic reactions that give biologically uncommon l-β-Asp, d-Asp, and d-β-Asp residues via the cyclic succinimide intermediate (aminosuccinyl residue, Suc). These abnormal Asp residues are known to have relevance
[...] Read more.
Aspartic acid (Asp) residues in proteins and peptides are prone to the non-enzymatic reactions that give biologically uncommon l-β-Asp, d-Asp, and d-β-Asp residues via the cyclic succinimide intermediate (aminosuccinyl residue, Suc). These abnormal Asp residues are known to have relevance to aging and pathologies. Despite being non-enzymatic, the Suc formation is thought to require a catalyst under physiological conditions. In this study, we computationally investigated the mechanism of the Suc formation from Asp residues that were catalyzed by the dihydrogen phosphate ion, H2PO4. We used Ac–l-Asp–NHMe (Ac = acetyl, NHMe = methylamino) as a model compound. The H2PO4 ion (as a catalyst) and two explicit water molecules (as solvent molecules stabilizing the negative charge) were included in the calculations. All of the calculations were performed by density functional theory with the B3LYP functional. We revealed a phosphate-catalyzed two-step mechanism (cyclization–dehydration) of the Suc formation, where the first step is predicted to be rate-determining. In both steps, the reaction involved a proton relay mediated by the H2PO4 ion. The calculated activation barrier for this mechanism (100.3 kJ mol−1) is in reasonable agreement with an experimental activation energy (107 kJ mol−1) for the Suc formation from an Asp-containing peptide in a phosphate buffer, supporting the catalytic mechanism of the H2PO4 ion that is revealed in this study. Full article
(This article belongs to the Section Molecular Biophysics)
Figures

Figure 1

Open AccessArticle Phytochemical Analysis by HPLC–HRESI-MS and Anti-Inflammatory Activity of Tabernaemontana catharinensis
Int. J. Mol. Sci. 2018, 19(2), 636; https://doi.org/10.3390/ijms19020636
Received: 22 November 2017 / Revised: 7 January 2018 / Accepted: 13 January 2018 / Published: 24 February 2018
PDF Full-text (3085 KB) | HTML Full-text | XML Full-text
Abstract
Tabernaemontana catharinensis (Apocynaceae) has been popularly used by folk medicine because of its anti-inflammatory, analgesic, and antiophidic properties. This study aims to analyze the flavonoids composition of the hydroethanolic extract and of the ethyl acetate (EtOAc) and butanol (BuOH) fractions of T. catharinensis
[...] Read more.
Tabernaemontana catharinensis (Apocynaceae) has been popularly used by folk medicine because of its anti-inflammatory, analgesic, and antiophidic properties. This study aims to analyze the flavonoids composition of the hydroethanolic extract and of the ethyl acetate (EtOAc) and butanol (BuOH) fractions of T. catharinensis leaves, as well as to evaluate their anti-inflammatory activity using in vivo models. The phytochemical profile, determined by High-Performance Liquid Chromatography–High-Resolution Electrospray Ionization-Mass Spectrometry (HPLC–HRESI-MS), showed the presence of flavonoids mainly having an isorhamnetin nucleus. The anti-inflammatory activity was evaluated in carrageenan-induced paw edema (pre- and post-treatment) with oral administration of a T. catharinensis hydroethanolic extract (50, 100, and 150 mg/kg) and of organic fractions (50 mg/kg). The extract and fractions showed antiedematogenic activity by decreasing myeloperoxidase (MPO) production. In the zymosan-air-pouch model, the extract and fractions inhibited leukocyte migration and significantly decreased the levels of various proteins, such as MPO, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α. The cytotoxicity was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, which revealed no cytotoxicity of the extract and the fractions. These results suggest that the hydroethanolic extract and organic fractions of T. catharinensis leaves have sufficient anti-inflammatory activity to support the popular use of this plant in the treatment of inflammatory disorders. Full article
(This article belongs to the Section Bioactives and Nutraceuticals)
Figures

Graphical abstract

Open AccessArticle The In Vitro Effects of Enzymatic Digested Gliadin on the Functionality of the Autophagy Process
Int. J. Mol. Sci. 2018, 19(2), 635; https://doi.org/10.3390/ijms19020635
Received: 22 January 2018 / Revised: 16 February 2018 / Accepted: 19 February 2018 / Published: 23 February 2018
PDF Full-text (9573 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Gliadin, the alcohol-soluble protein fraction of wheat, contains the factor toxic for celiac disease (CD), and its toxicity is not reduced by digestion with gastro-pancreatic enzymes. Importantly, it is proved that an innate immunity to gliadin plays a key role in the development
[...] Read more.
Gliadin, the alcohol-soluble protein fraction of wheat, contains the factor toxic for celiac disease (CD), and its toxicity is not reduced by digestion with gastro-pancreatic enzymes. Importantly, it is proved that an innate immunity to gliadin plays a key role in the development of CD. The immune response induces epithelial stress and reprograms intraepithelial lymphocytes into natural killer (NK)-like cells, leading to enterocyte apoptosis and an increase in epithelium permeability. In this contribution, we have reported that in Caco-2 cells the administration of enzymatically digested gliadin (PT-gliadin) reduced significantly the expression of the autophagy-related marker LC3-II. Furthermore, electron and fluorescent microscope analysis suggested a compromised functionality of the autophagosome apparatus. The rescue of the dysregulated autophagy process, along with a reduction of PT-gliadin toxicity, was obtained with a starvation induction protocol and by 3-methyladenine administration, while rapamycin, a well-known autophagy inducer, did not produce a significant improvement in the clearance of extra- and intra-cellular fluorescent PT-gliadin amount. Altogether, our results highlighted the possible contribution of the autophagy process in the degradation and in the reduction of extra-cellular release of gliadin peptides and suggest novel molecular targets to counteract gliadin-induced toxicity in CD. Full article
Figures

Graphical abstract

Open AccessArticle Sinus Bradycardia in Carriers of the SCN5A-1795insD Mutation: Unraveling the Mechanism through Computer Simulations
Int. J. Mol. Sci. 2018, 19(2), 634; https://doi.org/10.3390/ijms19020634
Received: 8 January 2018 / Revised: 13 February 2018 / Accepted: 19 February 2018 / Published: 23 February 2018
PDF Full-text (2722 KB) | HTML Full-text | XML Full-text
Abstract
The SCN5A gene encodes the pore-forming α-subunit of the ion channel that carries the cardiac fast sodium current (INa). The 1795insD mutation in SCN5A causes sinus bradycardia, with a mean heart rate of 70 beats/min in mutation carriers vs. 77
[...] Read more.
The SCN5A gene encodes the pore-forming α-subunit of the ion channel that carries the cardiac fast sodium current (INa). The 1795insD mutation in SCN5A causes sinus bradycardia, with a mean heart rate of 70 beats/min in mutation carriers vs. 77 beats/min in non-carriers from the same family (lowest heart rate 41 vs. 47 beats/min). To unravel the underlying mechanism, we incorporated the mutation-induced changes in INa into a recently developed comprehensive computational model of a single human sinoatrial node cell (Fabbri–Severi model). The 1795insD mutation reduced the beating rate of the model cell from 74 to 69 beats/min (from 49 to 43 beats/min in the simulated presence of 20 nmol/L acetylcholine). The mutation-induced persistent INa per se resulted in a substantial increase in beating rate. This gain-of-function effect was almost completely counteracted by the loss-of-function effect of the reduction in INa conductance. The further loss-of-function effect of the shifts in steady-state activation and inactivation resulted in an overall loss-of-function effect of the 1795insD mutation. We conclude that the experimentally identified mutation-induced changes in INa can explain the clinically observed sinus bradycardia. Furthermore, we conclude that the Fabbri–Severi model may prove a useful tool in understanding cardiac pacemaker activity in humans. Full article
(This article belongs to the Special Issue Ion Transporters and Channels in Physiology and Pathophysiology)
Figures

Graphical abstract

Open AccessReview On the Metal Cofactor in the Tyrosinase Family
Int. J. Mol. Sci. 2018, 19(2), 633; https://doi.org/10.3390/ijms19020633
Received: 26 January 2018 / Revised: 13 February 2018 / Accepted: 13 February 2018 / Published: 23 February 2018
Cited by 1 | PDF Full-text (852 KB) | HTML Full-text | XML Full-text
Abstract
The production of pigment in mammalian melanocytes requires the contribution of at least three melanogenic enzymes, tyrosinase and two other accessory enzymes called the tyrosinase-related proteins (Trp1 and Trp2), which regulate the type and amount of melanin. The last two proteins are paralogues
[...] Read more.
The production of pigment in mammalian melanocytes requires the contribution of at least three melanogenic enzymes, tyrosinase and two other accessory enzymes called the tyrosinase-related proteins (Trp1 and Trp2), which regulate the type and amount of melanin. The last two proteins are paralogues to tyrosinase, and they appeared late in evolution by triplication of the tyrosinase gene. Tyrosinase is a copper-enzyme, and Trp2 is a zinc-enzyme. Trp1 has been more elusive, and the direct identification of its metal cofactor has never been achieved. However, due to its enzymatic activity and similarities with tyrosinase, it has been assumed as a copper-enzyme. Recently, recombinant human tyrosinase and Trp1 have been expressed in enough amounts to achieve for the first time their crystallization. Unexpectedly, it has been found that Trp1 contains a couple of Zn(II) at the active site. This review discusses data about the metal cofactor of tyrosinase and Trps. It points out differences in the studied models, and it proposes some possible points accounting for the apparent discrepancies currently appearing. Moreover, some proposals about the possible flexibility of the tyrosinase family to uptake copper or zinc are discussed. Full article
(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)
Figures

Graphical abstract

Open AccessReview Alternative mRNA Splicing in the Pathogenesis of Obesity
Int. J. Mol. Sci. 2018, 19(2), 632; https://doi.org/10.3390/ijms19020632
Received: 5 January 2018 / Revised: 21 February 2018 / Accepted: 21 February 2018 / Published: 23 February 2018
PDF Full-text (1828 KB) | HTML Full-text | XML Full-text
Abstract
Alternative mRNA splicing is an important mechanism in expansion of proteome diversity by production of multiple protein isoforms. However, emerging evidence indicates that only a limited number of annotated protein isoforms by alternative splicing are detected, and the coding sequence of alternative splice
[...] Read more.
Alternative mRNA splicing is an important mechanism in expansion of proteome diversity by production of multiple protein isoforms. However, emerging evidence indicates that only a limited number of annotated protein isoforms by alternative splicing are detected, and the coding sequence of alternative splice variants usually is only slightly different from that of the canonical sequence. Nevertheless, mis-splicing is associated with a large array of human diseases. Previous reviews mainly focused on hereditary and somatic mutations in cis-acting RNA sequence elements and trans-acting splicing factors. The importance of environmental perturbations contributed to mis-splicing is not assessed. As significant changes in exon skipping and splicing factors expression levels are observed with diet-induced obesity, this review focuses on several well-known alternatively spliced metabolic factors and discusses recent advances in the regulation of the expressions of splice variants under the pathophysiological conditions of obesity. The potential of targeting the alternative mRNA mis-splicing for obesity-associated diseases therapies will also be discussed. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2017)
Figures

Figure 1

Open AccessReview Temporospatial Analysis and New Players in the Immunology of Amyotrophic Lateral Sclerosis
Int. J. Mol. Sci. 2018, 19(2), 631; https://doi.org/10.3390/ijms19020631
Received: 1 February 2018 / Revised: 18 February 2018 / Accepted: 21 February 2018 / Published: 23 February 2018
Cited by 1 | PDF Full-text (2945 KB) | HTML Full-text | XML Full-text
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of lower and upper motor neurons (MN) leading to muscle weakness, paralysis and eventually death. Although a highly varied etiology results in ALS, it broadly manifests itself as sporadic and familial
[...] Read more.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of lower and upper motor neurons (MN) leading to muscle weakness, paralysis and eventually death. Although a highly varied etiology results in ALS, it broadly manifests itself as sporadic and familial forms that have evident similarities in clinical symptoms and disease progression. There is a tremendous amount of knowledge on molecular mechanisms leading to loss of MNs and neuromuscular junctions (NMJ) as major determinants of disease onset, severity and progression in ALS. Specifically, two main opposing hypotheses, the dying forward and dying back phenomena, exist to account for NMJ denervation. The former hypothesis proposes that the earliest degeneration occurs at the central MNs and proceeds to the NMJ, whereas in the latter, the peripheral NMJ is the site of precipitating degeneration progressing backwards to the MN cell body. A large body of literature strongly indicates a role for the immune system in disease onset and progression via regulatory involvement at the level of both the central and peripheral nervous systems (CNS and PNS). In this review, we discuss the earliest reported immune responses with an emphasis on newly identified immune players in mutant superoxide dismutase 1 (mSOD1) transgenic mice, the gold standard mouse model for ALS. Full article
(This article belongs to the collection Neuroprotective Strategies)
Figures

Figure 1

Open AccessArticle Molecular Modeling Study for the Design of Novel Peroxisome Proliferator-Activated Receptor Gamma Agonists Using 3D-QSAR and Molecular Docking
Int. J. Mol. Sci. 2018, 19(2), 630; https://doi.org/10.3390/ijms19020630
Received: 30 January 2018 / Revised: 17 February 2018 / Accepted: 18 February 2018 / Published: 23 February 2018
PDF Full-text (2406 KB) | HTML Full-text | XML Full-text
Abstract
Type 2 diabetes is becoming a global pandemic disease. As an important target for the generation and development of diabetes mellitus, peroxisome proliferator-activated receptor γ (PPARγ) has been widely studied. PPARγ agonists have been designed as potential anti-diabetic agents. The advanced development of
[...] Read more.
Type 2 diabetes is becoming a global pandemic disease. As an important target for the generation and development of diabetes mellitus, peroxisome proliferator-activated receptor γ (PPARγ) has been widely studied. PPARγ agonists have been designed as potential anti-diabetic agents. The advanced development of PPARγ agonists represents a valuable research tool for diabetes therapy. To explore the structural requirements of PPARγ agonists, three-dimensional quantitative structure–activity relationship (3D-QSAR) and molecular docking studies were performed on a series of N-benzylbenzamide derivatives employing comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and surflex-dock techniques. The generated models of CoMFA and CoMSIA exhibited a high cross-validation coefficient (q2) of 0.75 and 0.551, and a non-cross-validation coefficient (r2) of 0.958 and 0.912, respectively. The predictive ability of the models was validated using external validation with predictive factor (r2pred) of 0.722 and 0.682, respectively. These results indicate that the model has high statistical reliability and good predictive power. The probable binding modes of the best active compounds with PPARγ active site were analyzed, and the residues His323, Tyr473, Ser289 and Ser342 were found to have hydrogen bond interactions. Based on the analysis of molecular docking results, and the 3D contour maps generated from CoMFA and CoMSIA models, the key structural features of PPARγ agonists responsible for biological activity could be determined, and several new molecules, with potentially higher predicted activity, were designed thereafter. This work may provide valuable information in further optimization of N-benzylbenzamide derivatives as PPARγ agonists. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
Figures

Graphical abstract

Open AccessReview Indispensable Role of Proteases in Plant Innate Immunity
Int. J. Mol. Sci. 2018, 19(2), 629; https://doi.org/10.3390/ijms19020629
Received: 5 February 2018 / Revised: 14 February 2018 / Accepted: 19 February 2018 / Published: 23 February 2018
PDF Full-text (2217 KB) | HTML Full-text | XML Full-text
Abstract
Plant defense is achieved mainly through the induction of microbe-associated molecular patterns (MAMP)-triggered immunity (MTI), effector-triggered immunity (ETI), systemic acquired resistance (SAR), induced systemic resistance (ISR), and RNA silencing. Plant immunity is a highly complex phenomenon with its own unique features that have
[...] Read more.
Plant defense is achieved mainly through the induction of microbe-associated molecular patterns (MAMP)-triggered immunity (MTI), effector-triggered immunity (ETI), systemic acquired resistance (SAR), induced systemic resistance (ISR), and RNA silencing. Plant immunity is a highly complex phenomenon with its own unique features that have emerged as a result of the arms race between plants and pathogens. However, the regulation of these processes is the same for all living organisms, including plants, and is controlled by proteases. Different families of plant proteases are involved in every type of immunity: some of the proteases that are covered in this review participate in MTI, affecting stomatal closure and callose deposition. A large number of proteases act in the apoplast, contributing to ETI by managing extracellular defense. A vast majority of the endogenous proteases discussed in this review are associated with the programmed cell death (PCD) of the infected cells and exhibit caspase-like activities. The synthesis of signal molecules, such as salicylic acid, jasmonic acid, and ethylene, and their signaling pathways, are regulated by endogenous proteases that affect the induction of pathogenesis-related genes and SAR or ISR establishment. A number of proteases are associated with herbivore defense. In this review, we summarize the data concerning identified plant endogenous proteases, their effect on plant-pathogen interactions, their subcellular localization, and their functional properties, if available, and we attribute a role in the different types and stages of innate immunity for each of the proteases covered. Full article
(This article belongs to the Special Issue Plant Innate Immunity 2.0)
Figures

Figure 1

Back to Top