International Journal of Molecular Sciences

17 pages, 4358 KiB

Open AccessArticle

Studies on the Interaction between Poly-Phosphane Gold(I) Complexes and Dihydrofolate Reductase: An Interplay with Nicotinamide Adenine Dinucleotide Cofactor

by Stefania Pucciarelli, Silvia Vincenzetti, Massimo Ricciutelli, Oumarou Camille Simon, Anna Teresa Ramadori, Lorenzo Luciani and Rossana Galassi

Int. J. Mol. Sci. 2019, 20(7), 1802; https://doi.org/10.3390/ijms20071802 - 11 Apr 2019

Cited by 3 | Viewed by 3961

Abstract

A class of gold(I) phosphane complexes have been identified as inhibitors of dihydrofolate reductase (DHFR) from E. coli, an enzyme that catalyzes the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF), using NADPH as a coenzyme. In this work, to comprehend the nature [...] Read more.

A class of gold(I) phosphane complexes have been identified as inhibitors of dihydrofolate reductase (DHFR) from E. coli, an enzyme that catalyzes the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF), using NADPH as a coenzyme. In this work, to comprehend the nature of the interaction at the basis of these inhibitory effects, the binding properties of bis- and tris-phosphane gold(I) chloride compounds in regards to DHFR have been studied by emission spectroscopy and spectrophotometric assays. The lack of cysteine and seleno-cysteine residues in the enzyme active site, the most favorable sites of attack of Au(I) moieties, makes this work noteworthy. The interaction with the gold compounds results into the quenching of the DHFR tryptophan’s emissions and in an enhancement of their intrinsic emission intensities. Moreover, a modulating action of NADPH is highlighted by means of an increase of the gold compound affinity toward the enzyme; in fact, the dissociation constants calculated for the interactions between DHFR and each gold compound in the presence of saturating NADPH were lower than the ones observed for the apo-enzyme. The fluorimetric data afforded to K_d values ranged from 2.22 ± 0.25 µM for (PPh₃)₂AuCl in the presence of NADPH to 21.4 ± 3.85 µM for ⁴L₃AuTf in the absence of NADPH. By elucidating the energetic aspects of the binding events, we have attempted to dissect the role played by the gold phosphane/protein interactions in the inhibitory activity, resulting in an exothermic enthalpy change and a positive entropic contribution (ΔH° = −5.04 ± 0.08 kcal/mol and ΔS° = 7.34 ± 0.005 cal/mol·K). Full article

(This article belongs to the Special Issue Interaction between Metal Compounds and Proteins)

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13 pages, 4129 KiB

Open AccessArticle

Molecular Cloning, Characterization, and Nutritional Regulation of Elovl6 in Large Yellow Croaker (Larimichthys crocea)

by Yongnan Li, Yuning Pang, Xiaojun Xiang, Jianlong Du, Kangsen Mai and Qinghui Ai

Int. J. Mol. Sci. 2019, 20(7), 1801; https://doi.org/10.3390/ijms20071801 - 11 Apr 2019

Cited by 33 | Viewed by 4675

Abstract

Elongation of very long chain fatty acids protein 6 (Elovl6) is a key enzyme in fatty acid synthesis, which participates in converting palmitate (C16:0) to stearate (C18:0). Although studies of Elovl6 have been carried out in mammals, the nutritional regulation of elovl6 in [...] Read more.

Elongation of very long chain fatty acids protein 6 (Elovl6) is a key enzyme in fatty acid synthesis, which participates in converting palmitate (C16:0) to stearate (C18:0). Although studies of Elovl6 have been carried out in mammals, the nutritional regulation of elovl6 in fish remains poorly understood. In the present study, the cloning and nutritional regulation of elovl6 were determined in large yellow croaker. Sequence and phylogenetic analysis revealed that the full-length cDNA of elovl6 was 1360 bp, including an open reading frame of 810 bp encoding a putative protein of 269 amino acid that possesses the characteristic features of Elovl proteins. The transcript level of elovl6 was significantly increased in the liver of croaker fed the diets with soybean oil (enriched with 18: 2n-6, LA) or linseed oil (enriched with 18: 3n-3, ALA) than that in croaker fed the diet with fish oil (enriched with 20: 5n-3 and 22: 6n-3). Correspondingly, the elovl6 expression in croaker’s hepatocytes treated with ALA or LA was remarkably increased compared to the controls. Furthermore, the transcription factors including hepatocyte nuclear factor 1α (HNF1α), CCAAT-enhancer-binding protein β (CEBPβ), retinoid X receptor α (RXRα), and cAMP response element-binding protein 1 (CREB1) greatly enhanced promoter activity of elovl6 in large yellow croaker, and the expression of transcription factors is consistent with the changes of elovl6 expression in response to fatty acids in vivo and in vitro. In conclusion, this study revealed that elovl6 expression in large yellow croaker could be upregulated by dietary ALA or LA via the increased transcriptional expression of transcription factors including hnf1α, cebpβ, rxrα, and creb1. Full article

(This article belongs to the Section Molecular Biology)

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14 pages, 4550 KiB

Open AccessArticle

L-Arginine Inhibited Inflammatory Response and Oxidative Stress Induced by Lipopolysaccharide via Arginase-1 Signaling in IPEC-J2 Cells

by Yueqin Qiu, Xuefen Yang, Li Wang, Kaiguo Gao and Zongyong Jiang

Int. J. Mol. Sci. 2019, 20(7), 1800; https://doi.org/10.3390/ijms20071800 - 11 Apr 2019

Cited by 86 | Viewed by 5633

Abstract

This study aimed to explore the effect of L-arginine on lipopolysaccharide (LPS)-induced inflammatory response and oxidative stress in IPEC-2 cells. We found that the expression of toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), cluster of differentiation [...] Read more.

This study aimed to explore the effect of L-arginine on lipopolysaccharide (LPS)-induced inflammatory response and oxidative stress in IPEC-2 cells. We found that the expression of toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), cluster of differentiation 14 (CD14), nuclear factor-kappaBp65 (NF-κBp65), chemokine-8 (IL-8), tumor necrosis factor (TNF-α) and chemokine-6 (IL-6) mRNA were significantly increased by LPS. Exposure to LPS induced oxidative stress as reactive oxygen species (ROS) and malonaldehyde (MDA) production were increased while glutathione peroxidase (GSH-Px) were decreased in LPS-treated cells compared to those in the control. LPS administration also effectively induced cell growth inhibition through induction of G0/G1 cell cycle arrest. However, compared with the LPS group, cells co-treatment with L-arginine effectively increased cell viability and promoted the cell cycle into the S phase; L-arginine exhibited an anti-inflammatory effect in alleviating inflammation induced by LPS by reducing the abundance of TLR4, MyD88, CD14, NF-κBp65, and IL-8 transcripts. Cells treated with LPS+L-arginine significantly enhanced the content of GSH-Px, while they decreased the production of ROS and MDA compared with the LPS group. Furthermore, L-arginine increased the activity of arginase-1 (Arg-1), while Arg-1 inhibitor abolished the protection of arginine against LPS-induced inflammation and oxidative stress. Taken together, these results suggested that L-arginine exerted its anti-inflammatory and antioxidant effects to protect IPEC-J2 cells from inflammatory response and oxidative stress challenged by LPS at least partly via the Arg-1 signaling pathway. Full article

(This article belongs to the Section Biochemistry)

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19 pages, 5088 KiB

Open AccessArticle

Low-Luminance Blue Light-Enhanced Phototoxicity in A2E-Laden RPE Cell Cultures and Rats

by Cheng-Hui Lin, Man-Ru Wu, Wei-Jan Huang, Diana Shu-Lian Chow, George Hsiao and Yu-Wen Cheng

Int. J. Mol. Sci. 2019, 20(7), 1799; https://doi.org/10.3390/ijms20071799 - 11 Apr 2019

Cited by 31 | Viewed by 7448

Abstract

N-retinylidene-N-retinylethanolamine (A2E) and other bisretinoids are components of lipofuscin and accumulate in retinal pigment epithelial (RPE) cells—these adducts are recognized in the pathogenesis of retinal degeneration. Further, blue light-emitting diode (LED) light (BLL)-induced retinal toxicity plays an important role in retinal degeneration. Here, [...] Read more.

N-retinylidene-N-retinylethanolamine (A2E) and other bisretinoids are components of lipofuscin and accumulate in retinal pigment epithelial (RPE) cells—these adducts are recognized in the pathogenesis of retinal degeneration. Further, blue light-emitting diode (LED) light (BLL)-induced retinal toxicity plays an important role in retinal degeneration. Here, we demonstrate that low-luminance BLL enhances phototoxicity in A2E-laden RPE cells and rats. RPE cells were subjected to synthetic A2E, and the effects of BLL on activation of apoptotic biomarkers were examined by measuring the levels of cleaved caspase-3. BLL modulates the protein expression of zonula-occludens 1 (ZO-1) and paracellular permeability in A2E-laden RPE cells. Early inflammatory and angiogenic genes were also screened after short-term BLL exposure. In this study, we developed a rat model for A2E treatment with or without BLL exposure for 21 days. BLL exposure caused fundus damage, decreased total retinal thickness, and caused neuron transduction injury in the retina, which were consistent with the in vitro data. We suggest that the synergistic effects of BLL and A2E accumulation in the retina increase the risk of retinal degeneration. These outcomes help elucidate the associations between BLL/A2E and angiogenic/apoptotic mechanisms, as well as furthering therapeutic strategies. Full article

(This article belongs to the Special Issue Biochemistry, Molecular Biology and Toxicology of Natural and Synthetic Toxins)

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17 pages, 2458 KiB

Open AccessArticle

Activation of PPARs Modulates Signalling Pathways and Expression of Regulatory Genes in Osteoclasts Derived from Human CD14+ Monocytes

by Abe Kasonga, Marlena C. Kruger and Magdalena Coetzee

Int. J. Mol. Sci. 2019, 20(7), 1798; https://doi.org/10.3390/ijms20071798 - 11 Apr 2019

Cited by 25 | Viewed by 4299

Abstract

Osteoclasts are the sole bone resorbing cell in the body and their over activity is key in the development of osteoporosis. Osteoclastogenesis is mediated by receptor activator of nuclear factor κB ligand (RANKL) signalling pathways. Unsaturated fatty acids (UFA) are known to inhibit [...] Read more.

Osteoclasts are the sole bone resorbing cell in the body and their over activity is key in the development of osteoporosis. Osteoclastogenesis is mediated by receptor activator of nuclear factor κB ligand (RANKL) signalling pathways. Unsaturated fatty acids (UFA) are known to inhibit osteoclastogenesis by targeting RANKL signalling. However, the mechanisms of action remain unclear. Peroxisome proliferator activated receptors (PPARs) are a family of nuclear receptors, with three known isoforms (PPAR-α, PPAR-β/δ and PPAR-γ), that are known to bind UFAs and are expressed in osteoclasts. In this study, we aimed to determine how different families of UFAs activate PPARs and how PPAR activation influences osteoclast signalling. Human CD14+ monocytes were seeded into cluster plates with RANKL and macrophage colony stimulating factor (M-CSF) in the presence of PPAR agonists or different types of UFAs. All the PPAR agonists were shown to upregulate the activity of their respective receptors. Polyunsaturated fatty acids increased PPAR-α to a greater extent than monounsaturated fatty acids (MUFAs), which favoured PPAR-β/δ activation. All PPAR agonists inhibited osteoclastogenesis. The activation of RANKL signalling pathways and expression of key osteoclast genes were downregulated by PPAR agonists. This study reveals that PPAR activation can inhibit osteoclastogenesis through modulation of RANKL signalling. Full article

(This article belongs to the Special Issue Osteoporosis: From Molecular Mechanisms to Therapies)

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12 pages, 3226 KiB

Open AccessArticle

Altered Glutamate Receptor Ionotropic Delta Subunit 2 Expression in Stau2-Deficient Cerebellar Purkinje Cells in the Adult Brain

by Helena F. Pernice, Rico Schieweck, Mehrnoosh Jafari, Tobias Straub, Martin Bilban, Michael A. Kiebler and Bastian Popper

Int. J. Mol. Sci. 2019, 20(7), 1797; https://doi.org/10.3390/ijms20071797 - 11 Apr 2019

Cited by 10 | Viewed by 4928

Abstract

Staufen2 (Stau2) is an RNA-binding protein that is involved in dendritic spine morphogenesis and function. Several studies have recently investigated the role of Stau2 in the regulation of its neuronal target mRNAs, with particular focus on the hippocampus. Here, we provide evidence for [...] Read more.

Staufen2 (Stau2) is an RNA-binding protein that is involved in dendritic spine morphogenesis and function. Several studies have recently investigated the role of Stau2 in the regulation of its neuronal target mRNAs, with particular focus on the hippocampus. Here, we provide evidence for Stau2 expression and function in cerebellar Purkinje cells. We show that Stau2 downregulation (Stau2^GT) led to an increase of glutamate receptor ionotropic delta subunit 2 (GluD2) in Purkinje cells when animals performed physical activity by voluntary wheel running compared with the age-matched wildtype (WT) mice (C57Bl/6J). Furthermore, Stau2^GT mice showed lower performance in motor coordination assays but enhanced motor learning abilities than did WT mice, concomitantly with an increase in dendritic GluD2 expression. Together, our results suggest the novel role of Stau2 in Purkinje cell synaptogenesis in the mouse cerebellum. Full article

(This article belongs to the Section Molecular Neurobiology)

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13 pages, 925 KiB

Open AccessReview

Glutamate Receptors and Glioblastoma Multiforme: An Old “Route” for New Perspectives

by Lorenzo Corsi, Andrea Mescola and Andrea Alessandrini

Int. J. Mol. Sci. 2019, 20(7), 1796; https://doi.org/10.3390/ijms20071796 - 11 Apr 2019

Cited by 45 | Viewed by 6680

Abstract

Glioblastoma multiforme (GBM) is the most aggressive malignant tumor of the central nervous system, with poor survival in both treated and untreated patients. Recent studies began to explain the molecular pathway, comprising the dynamic structural and mechanical changes involved in GBM. In this [...] Read more.

Glioblastoma multiforme (GBM) is the most aggressive malignant tumor of the central nervous system, with poor survival in both treated and untreated patients. Recent studies began to explain the molecular pathway, comprising the dynamic structural and mechanical changes involved in GBM. In this context, some studies showed that the human glioblastoma cells release high levels of glutamate, which regulates the proliferation and survival of neuronal progenitor cells. Considering that cancer cells possess properties in common with neural progenitor cells, it is likely that the functions of glutamate receptors may affect the growth of cancer cells and, therefore, open the road to new and more targeted therapies. Full article

(This article belongs to the Special Issue Glutamate Receptors in Health and Disease)

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20 pages, 5813 KiB

Open AccessArticle

Bone Marrow Endothelial Cells Influence Function and Phenotype of Hematopoietic Stem and Progenitor Cells after Mixed Neutron/Gamma Radiation

by Lynnette Cary, Daniel Noutai, Rudolph Salber, Opeyemi Fadiyimu, Arthur Gross, Graca Almeida-Porada, Yared Kidane and Mark Whitnall

Int. J. Mol. Sci. 2019, 20(7), 1795; https://doi.org/10.3390/ijms20071795 - 11 Apr 2019

Cited by 10 | Viewed by 4719

Abstract

The bone marrow (BM) microenvironment plays a crucial role in the maintenance and regeneration of hematopoietic stem (HSC) and progenitor cells (HSPC). In particular, the vascular niche is responsible for regulating HSC maintenance, differentiation, and migration of cells in and out of the [...] Read more.

The bone marrow (BM) microenvironment plays a crucial role in the maintenance and regeneration of hematopoietic stem (HSC) and progenitor cells (HSPC). In particular, the vascular niche is responsible for regulating HSC maintenance, differentiation, and migration of cells in and out of the BM. Damage to this niche upon exposure to ionizing radiation, whether accidental or as a result of therapy, can contribute to delays in HSC recovery and/or function. The ability of BM derived-endothelial cells (BMEC) to alter and/or protect HSPC after exposure to ionizing radiation was investigated. Our data show that exposure of BMEC to ionizing radiation resulted in alterations in Akt signaling, increased expression of PARP-1, IL6, and MCP-1, and decreased expression of MMP1 and MMP9. In addition, global analysis of gene expression of HSC and BMEC in response to mixed neutron/gamma field (MF) radiation identified 60 genes whose expression was altered after radiation in both cell types, suggesting that a subset of genes is commonly affected by this type of radiation. Focused gene analysis by RT-PCR revealed two categories of BMEC alterations: (a) a subset of genes whose expression was altered in response to radiation, with no additional effect observed during coculture with HSPC, and (b) a subset of genes upregulated in response to radiation, and altered when cocultured with HSPC. Coculture of BMEC with CD34+ HSPC induced HSPC proliferation, and improved BM function after MF radiation. Nonirradiated HSPC exhibited reduced CD34 expression over time, but when irradiated, they maintained higher CD34 expression. Nonirradiated HSPC cocultured with nonirradiated BMEC expressed lower levels of CD34 expression compared to nonirradiated alone. These data characterize the role of each cell type in response to MF radiation and demonstrate the interdependence of each cell’s response to ionizing radiation. The identified genes modulated by radiation and coculture provide guidance for future experiments to test hypotheses concerning specific factors mediating the beneficial effects of BMEC on HSPC. This information will prove useful in the search for medical countermeasures to radiation-induced hematopoietic injury. Full article

(This article belongs to the Collection Radiation Toxicity in Cells)

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12 pages, 951 KiB

Open AccessArticle

Hydrodynamic Behavior of the Intrinsically Disordered Potyvirus Protein VPg, of the Translation Initiation Factor eIF4E and of their Binary Complex

by Jocelyne Walter, Amandine Barra, Bénédicte Doublet, Nicolas Céré, Justine Charon and Thierry Michon

Int. J. Mol. Sci. 2019, 20(7), 1794; https://doi.org/10.3390/ijms20071794 - 11 Apr 2019

Cited by 6 | Viewed by 3757

Abstract

Protein intrinsic disorder is involved in many biological processes and good experimental models are valuable to investigate its functions. The potyvirus genome-linked protein, VPg, displays many features of an intrinsically disordered protein. The virus cycle requires the formation of a complex between VPg [...] Read more.

Protein intrinsic disorder is involved in many biological processes and good experimental models are valuable to investigate its functions. The potyvirus genome-linked protein, VPg, displays many features of an intrinsically disordered protein. The virus cycle requires the formation of a complex between VPg and eIF4E, one of the host translation initiation factors. An in-depth characterization of the hydrodynamic properties of VPg, eIF4E, and of their binary complex VPg-eIF4E was carried out. Two complementary experimental approaches, size-exclusion chromatography and fluorescence anisotropy, which is more resolving and revealed especially suitable when protein concentration is the limiting factor, allowed to estimate monomers compaction upon complex formation. VPg possesses a high degree of hydration which is in agreement with its classification as a partially folded protein in between a molten and pre-molten globule. The natively disordered first 46 amino acids of eIF4E contribute to modulate the protein hydrodynamic properties. The addition of an N-ter His tag decreased the conformational entropy of this intrinsically disordered region. A comparative study between the two tagged and untagged proteins revealed the His tag contribution to proteins hydrodynamic behavior. Full article

(This article belongs to the Special Issue Functionally Relevant Macromolecular Interactions of Disordered Proteins)

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20 pages, 4616 KiB

Open AccessArticle

Cerebrospinal Fluid (CSF) Exchange with Artificial CSF Enriched with Mesenchymal Stem Cell Secretions Ameliorates Experimental Autoimmune Encephalomyelitis

by Michael Valitsky, Sandrine Benhamron, Keren Nitzan, Dimitrios Karussis, Ezra Ella, Oded Abramsky, Ibrahim Kassis and Hanna Rosenmann

Int. J. Mol. Sci. 2019, 20(7), 1793; https://doi.org/10.3390/ijms20071793 - 11 Apr 2019

Cited by 9 | Viewed by 4684

Abstract

The complexity of central nervous system (CNS) degenerative/inflammatory diseases and the lack of substantially effective treatments point to the need for a broader therapeutic approach to target multiple components involved in the disease pathogenesis. We suggest a novel approach directed for the elimination [...] Read more.

The complexity of central nervous system (CNS) degenerative/inflammatory diseases and the lack of substantially effective treatments point to the need for a broader therapeutic approach to target multiple components involved in the disease pathogenesis. We suggest a novel approach directed for the elimination of pathogenic agents from the CNS and, in parallel, its enrichment with an array of neuroprotective substances, using a “cerebrospinal fluid (CSF) exchange” procedure, in which endogenous (pathogenic) CSF is removed and replaced by artificial CSF (aCSF) enriched with secretions of human mesenchymal stem cells (MSCs). MSCs produce a variety of neuroprotective agents and have shown beneficial effects when cells are transplanted in animals and patients with CNS diseases. Our data show that MSCs grown in aCSF secrete neurotrophic factors, anti-inflammatory cytokines, and anti-oxidant agents; moreover, MSC-secretions-enriched-aCSF exerts neuroprotective and immunomodulatory effects in neuronal cell lines and spleen lymphocytes. Treatment of experimental-autoimmune-encephalomyelitis (EAE) mice with this enriched-aCSF using an intracerebroventricular (ICV) CSF exchange procedure (“CSF exchange therapy”) caused a significant delay in the onset of EAE and amelioration of the clinical symptoms, paralleled by a reduction in axonal damage and demyelination. These findings point to the therapeutic potential of the CSF exchange therapy using MSC-secretions-enriched-aCSF in inflammatory/degenerative diseases of the CNS. Full article

(This article belongs to the Section Molecular Neurobiology)

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25 pages, 1872 KiB

Open AccessReview

Stressed: The Unfolded Protein Response in T Cell Development, Activation, and Function

by Kyeorda Kemp and Cody Poe

Int. J. Mol. Sci. 2019, 20(7), 1792; https://doi.org/10.3390/ijms20071792 - 11 Apr 2019

Cited by 32 | Viewed by 8063

Abstract

The unfolded protein response (UPR) is a highly conserved pathway that allows cells to respond to stress in the endoplasmic reticulum caused by an accumulation of misfolded and unfolded protein. This is of great importance to secretory cells because, in order for proteins [...] Read more.

The unfolded protein response (UPR) is a highly conserved pathway that allows cells to respond to stress in the endoplasmic reticulum caused by an accumulation of misfolded and unfolded protein. This is of great importance to secretory cells because, in order for proteins to traffic from the endoplasmic reticulum (ER), they need to be folded appropriately. While a wealth of literature has implicated UPR in immune responses, less attention has been given to the role of UPR in T cell development and function. This review discusses the importance of UPR in T cell development, homeostasis, activation, and effector functions. We also speculate about how UPR may be manipulated in T cells to ameliorate pathologies. Full article

(This article belongs to the Special Issue Molecular Regulation of the Endomembrane System)

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19 pages, 1327 KiB

Open AccessArticle

Cryopreservation Differentially Alters the Proteome of Epididymal and Ejaculated Pig Spermatozoa

by Cristina Perez-Patiño, Isabel Barranco, Junwei Li, Lorena Padilla, Emilio A. Martinez, Heriberto Rodriguez-Martinez, Jordi Roca and Inmaculada Parrilla

Int. J. Mol. Sci. 2019, 20(7), 1791; https://doi.org/10.3390/ijms20071791 - 11 Apr 2019

Cited by 37 | Viewed by 4891

Abstract

Cryopreservation induces differential remodeling of the proteome in mammalian spermatozoa. How these proteome changes relate to the loss of sperm function during cryopreservation remains unsolved. The present study aimed to clarify this issue evaluating differential changes in the proteome of fresh and frozen-thawed [...] Read more.

Cryopreservation induces differential remodeling of the proteome in mammalian spermatozoa. How these proteome changes relate to the loss of sperm function during cryopreservation remains unsolved. The present study aimed to clarify this issue evaluating differential changes in the proteome of fresh and frozen-thawed pig spermatozoa retrieved from the cauda epididymis and the ejaculate of the same boars, with clear differences in cryotolerance. Spermatozoa were collected from 10 healthy, sexually mature, and fertile boars, and cryopreserved using a standard 0.5 mL-straw protocol. Total and progressive motility, viability, and mitochondria membrane potential were higher and membrane fluidity and reactive oxygen species generation lower in frozen-thawed (FT) epididymal than ejaculated spermatozoa. Quantitative proteomics of fresh and FT spermatozoa were analyzed using a LC-ESI-MS/MS-based Sequential Window Acquisition of All Theoretical Spectra approach. Cryopreservation quantitatively altered more proteins in ejaculated than cauda epididymal spermatozoa. Differential protein–protein networks highlighted a set of proteins quantitatively altered in ejaculated spermatozoa, directly involved in mitochondrial functionality which would explain why ejaculated spermatozoa deteriorate during cryopreservation. Full article

(This article belongs to the Special Issue Molecular Biology of Spermatozoa)

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23 pages, 10633 KiB

Open AccessArticle

Development, Characterization and In Vitro Biological Properties of Scaffolds Fabricated From Calcium Phosphate Nanoparticles

by Lizette Morejón, José Angel Delgado, Alexandre Antunes Ribeiro, Marize Varella de Oliveira, Eduardo Mendizábal, Ibrahim García, Adrián Alfonso, Patrina Poh, Martijn van Griensven and Elizabeth R. Balmayor

Int. J. Mol. Sci. 2019, 20(7), 1790; https://doi.org/10.3390/ijms20071790 - 11 Apr 2019

Cited by 38 | Viewed by 4747

Abstract

Ceramic materials mimic the mineral composition of native bone and feature osteoconductive properties; they are therefore used to regenerate bone tissue. Much research focuses on increasing the porosity and pore interconnectivity of ceramic scaffolds to increase osteoconductivity, cell migration and cell-cell interaction. We [...] Read more.

Ceramic materials mimic the mineral composition of native bone and feature osteoconductive properties; they are therefore used to regenerate bone tissue. Much research focuses on increasing the porosity and pore interconnectivity of ceramic scaffolds to increase osteoconductivity, cell migration and cell-cell interaction. We aimed to fabricate biocompatible 3D-scaffolds featuring macro- and microporous calcium phosphates with high pore interconnection. Nanoparticles of hydroxyapatite (HA) and calcium deficient hydroxyapatite (CDHA) were synthesized by wet chemical precipitation. Scaffolds were produced from them by the replication polymeric foam technique. Solid content and sintering temperature were varied. Nanoparticles and scaffolds were characterized regarding morphology, chemical and mineral composition, porosity and mechanical properties. Biocompatibility, cell attachment and distribution were evaluated in vitro with human adipose mesenchymal stem cells. Scaffolds with total porosity of 71%–87%, pores in the range of 280–550 µm and connectivity density up to 43 mm⁻³ were obtained. Smaller pore sizes were obtained at higher sintering temperature. High solid content resulted in a decrease of total porosity but increased interconnectivity. Scaffolds 50HA/50β-TCP featured superior interconnectivity and mechanical properties. They were bioactive and biocompatible. High HA solid content (40 wt.%) in the HA pure scaffolds was negative for cell viability and proliferation, while in the 50HA/50β-TCP composite scaffolds it resulted more biocompatible. Full article

(This article belongs to the Special Issue Biomaterials for Musculoskeletal System)

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17 pages, 3697 KiB

Open AccessArticle

Complementary Transcriptomic and Proteomic Analysis Reveals a Complex Network Regulating Pollen Abortion in GMS (msc-1) Pepper (Capsicum annuum L.)

by Qing Cheng, Ting Li, Yixin Ai, Qiaohua Lu, Yihao Wang, Liang Sun and Huolin Shen

Int. J. Mol. Sci. 2019, 20(7), 1789; https://doi.org/10.3390/ijms20071789 - 11 Apr 2019

Cited by 11 | Viewed by 4227

Abstract

Pepper (Capsicum annuum L.) is a globally important horticultural crop. Use of the genic male-sterile (GMS) line enables efficient commercial hybrid pepper seed production. However, the mechanisms of pepper GMS functioning remain unclear. In this study, we used proteomic and transcriptomic analysis [...] Read more.

Pepper (Capsicum annuum L.) is a globally important horticultural crop. Use of the genic male-sterile (GMS) line enables efficient commercial hybrid pepper seed production. However, the mechanisms of pepper GMS functioning remain unclear. In this study, we used proteomic and transcriptomic analysis to identify proteins and genes related to genic male sterility. A total of 764 differentially expressed proteins (DEPs) and 1069 differentially expressed genes (DEGs) were identified in the proteomic and transcriptomic level respectively, and 52 genes (hereafter “cor-DEGs-DEPs” genes) were detected at both levels. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified 13 DEPs and 14 DEGs involved in tapetum and pollen development. Among the 13 DEPs identified, eight were involved in pollen exine formation, and they were all up-regulated in the fertile line 16C1369B. For the 14 DEGs identified, ABORTED MICROSPORES (AMS) and DEFECTIVE IN TAPETAL DEVELOPMENT AND FUNCTION1 (TDF1) were involved in tapetum development, and both are possibly regulated by Msc-1. All of these genes were detected and confirmed by qRT-PCR. The presence of these genes suggests their possible role in tapetum and pollen exine formation in GMS pepper. Most key genes and transcription factors involved in these processes were down-regulated in the sterile line 16C1369A. This study provides a better understanding of GMS (msc-1) molecular functioning in pepper. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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17 pages, 4561 KiB

Open AccessArticle

Effects of Naphthazarin (DHNQ) Combined with Lawsone (NQ-2-OH) or 1,4-Naphthoquinone (NQ) on the Auxin-Induced Growth of Zea mays L. Coleoptile Segments

by Małgorzata Rudnicka, Michał Ludynia and Waldemar Karcz

Int. J. Mol. Sci. 2019, 20(7), 1788; https://doi.org/10.3390/ijms20071788 - 11 Apr 2019

Cited by 10 | Viewed by 4977

Abstract

Naphthoquinones, plants secondary metabolites are known for their antibacterial, antifungal, anti-inflammatory, anti-cancer and anti-parasitic properties. The biological activity of naphthoquinones is connected with their ability to generate reactive oxygen species and to modify biological molecules at their nucleophilic sites. In our research, the [...] Read more.

Naphthoquinones, plants secondary metabolites are known for their antibacterial, antifungal, anti-inflammatory, anti-cancer and anti-parasitic properties. The biological activity of naphthoquinones is connected with their ability to generate reactive oxygen species and to modify biological molecules at their nucleophilic sites. In our research, the effect of naphthazarin (DHNQ) combined with 2-hydroxy-1,4-naphthoquinone (NQ-2-OH) or 1,4-naphthoquinone (1,4-NQ) on the elongation growth, pH changes of the incubation medium, oxidative stress and redox activity of maize coleoptile cells were investigated. This paper describes experiments performed with maize (Zea mays L.) coleoptile segments, which is a classical model system to study plant cell elongation growth. The data presented clearly demonstrate that lawsone and 1,4-naphthoquinone combined with naphthazarin, at low concentrations (1 and 10 nM), reduced the endogenous and IAA-induced (Indole-3-Acetic Acid) elongation growth of maize coleoptile segments. Those changes in growth correlated with the proton concentration in the incubation medium, which suggests that the changes in the growth of maize coleoptile segments observed in the presence of naphthoquinones are mediated through the activity of PM H⁺-ATPase. The presence of naphthoquinones induced oxidative stress in the maize coleoptile tissue by producing hydrogen peroxide and causing changes in the redox activity. Moreover, the incubation of maize segments with both naphthoquinones combined with naphthazarin resulted in lipid peroxidation and membrane damage. The regulation of PM H⁺-ATPase activity, especially its inhibition, may result from two major types of reaction: first, a direct interaction between an enzyme and naphthoquinone, which leads to the covalent modification of the protein thiols and the generation of thioethers, which have been found to alter the activity of the PM H⁺-ATPases; second, naphthoquinones induce reactive oxygen species (ROS) production, which inhibits PM H⁺-ATPases by increasing cytosolic Ca²⁺. This harmful effect was stronger when naphthazarin and 1,4-naphthoquinone were added together. Taking these results into account, it can be suggested that by combining naphthoquinones in small quantities, an alternative to synthetic pesticides could be developed. Full article

(This article belongs to the Special Issue Phytohormones and Their Crosstalk during Plant Growth, Development and Environmental Stress Adaptation: New Prospects and Challenges to Cope with Global Climate Change)

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19 pages, 4176 KiB

Open AccessArticle

Effect of Ultraviolet-C Radiation and Melatonin Stress on Biosynthesis of Antioxidant and Antidiabetic Metabolites Produced in In Vitro Callus Cultures of Lepidium sativum L.

by Muhammad Asad Ullah, Duangjai Tungmunnithum, Laurine Garros, Samantha Drouet, Christophe Hano and Bilal Haider Abbasi

Int. J. Mol. Sci. 2019, 20(7), 1787; https://doi.org/10.3390/ijms20071787 - 11 Apr 2019

Cited by 58 | Viewed by 6129

Abstract

Lepidium sativum L. is a rich source of polyphenols that have huge medicinal and pharmaceutical applications. In the current study, an effective abiotic elicitation strategy was designed for enhanced biosynthesis of polyphenols in callus culture of L. sativum. Callus was exposed to [...] Read more.

Lepidium sativum L. is a rich source of polyphenols that have huge medicinal and pharmaceutical applications. In the current study, an effective abiotic elicitation strategy was designed for enhanced biosynthesis of polyphenols in callus culture of L. sativum. Callus was exposed to UV-C radiations for different time intervals and various concentrations of melatonin. Secondary metabolites were quantified by using high-performance liquid chromatography (HPLC). Results indicated the total secondary metabolite accumulation of nine quantified compounds was almost three fold higher (36.36 mg/g dry weight (DW)) in melatonin (20 μM) treated cultures, whereas, in response to UV-C (60 min), a 2.5 fold increase (32.33 mg/g DW) was recorded compared to control (13.94 mg/g DW). Metabolic profiling revealed the presence of three major phytochemicals, i.e., chlorogenic acid, kaemferol, and quercetin, in callus culture of L. sativum. Furthermore, antioxidant, antidiabetic, and enzymatic activities of callus cultures were significantly enhanced. Maximum antidiabetic activities (α-glucosidase: 57.84%; α-amylase: 62.66%) were recorded in melatonin (20 μM) treated callus cultures. Overall, melatonin proved to be an effect elicitor compared to UV-C and a positive correlation in these biological activities and phytochemical accumulation was observed. The present study provides a better comparison of both elicitors and their role in the initiation of physiological pathways for enhanced metabolites biosynthesis in vitro callus culture of L. sativum. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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16 pages, 2323 KiB

Open AccessArticle

Prediction of Bioactive Peptides from Chlorella sorokiniana Proteins Using Proteomic Techniques in Combination with Bioinformatics Analyses

by Lhumen A. Tejano, Jose P. Peralta, Encarnacion Emilia S. Yap, Fenny Crista A. Panjaitan and Yu-Wei Chang

Int. J. Mol. Sci. 2019, 20(7), 1786; https://doi.org/10.3390/ijms20071786 - 11 Apr 2019

Cited by 55 | Viewed by 7311

Abstract

Chlorella is one of the most nutritionally important microalgae with high protein content and can be a good source of potential bioactive peptides. In the current study, isolated proteins from Chlorella sorokiniana were subjected to in silico analysis to predict potential peptides with [...] Read more.

Chlorella is one of the most nutritionally important microalgae with high protein content and can be a good source of potential bioactive peptides. In the current study, isolated proteins from Chlorella sorokiniana were subjected to in silico analysis to predict potential peptides with biological activities. Molecular characteristics of proteins were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and proteomics techniques. A total of eight proteins were identified by proteomics techniques from 10 protein bands of the SDS-PAGE. The predictive result by BIOPEP’s profile of bioactive peptides tools suggested that proteins of C. sorokiniana have the highest number of dipeptidyl peptidase-IV (DPP IV) inhibitors, with high occurrence of other bioactive peptides such as angiotensin-I converting enzyme (ACE) inhibitor, glucose uptake stimulant, antioxidant, regulating, anti-amnestic and antithrombotic peptides. In silico analysis of enzymatic hydrolysis revealed that pepsin (pH > 2), bromelain and papain were proteases that can release relatively larger quantity of bioactive peptides. In addition, combinations of different enzymes in hydrolysis were observed to dispense higher numbers of bioactive peptides from proteins compared to using individual proteases. Results suggest the potential of protein isolated from C. sorokiniana could be a source of high value products with pharmaceutical and nutraceutical application potential. Full article

(This article belongs to the Special Issue Peptides for Health Benefits 2019)

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27 pages, 1126 KiB

Open AccessReview

Mitogen Activated Protein Kinases in Steatotic and Non-Steatotic Livers Submitted to Ischemia-Reperfusion

by Mónica B. Jiménez-Castro, María Eugenia Cornide-Petronio, Jordi Gracia-Sancho, Araní Casillas-Ramírez and Carmen Peralta

Int. J. Mol. Sci. 2019, 20(7), 1785; https://doi.org/10.3390/ijms20071785 - 10 Apr 2019

Cited by 27 | Viewed by 4770

Abstract

We analyzed the participation of mitogen-activated protein kinases (MAPKs), namely p38, JNK and ERK 1/2 in steatotic and non-steatotic livers undergoing ischemia-reperfusion (I-R), an unresolved problem in clinical practice. Hepatic steatosis is a major risk factor in liver surgery because these types of [...] Read more.

We analyzed the participation of mitogen-activated protein kinases (MAPKs), namely p38, JNK and ERK 1/2 in steatotic and non-steatotic livers undergoing ischemia-reperfusion (I-R), an unresolved problem in clinical practice. Hepatic steatosis is a major risk factor in liver surgery because these types of liver tolerate poorly to I-R injury. Also, a further increase in the prevalence of steatosis in liver surgery is to be expected. The possible therapies based on MAPK regulation aimed at reducing hepatic I-R injury will be discussed. Moreover, we reviewed the relevance of MAPK in ischemic preconditioning (PC) and evaluated whether MAPK regulators could mimic its benefits. Clinical studies indicated that this surgical strategy could be appropriate for liver surgery in both steatotic and non-steatotic livers undergoing I-R. The data presented herein suggest that further investigations are required to elucidate more extensively the mechanisms by which these kinases work in hepatic I-R. Also, further researchers based in the development of drugs that regulate MAPKs selectively are required before such approaches can be translated into clinical liver surgery. Full article

(This article belongs to the Special Issue Pathophysiological and Molecular Mechanisms in Non-alcoholic Fatty Liver Disease)

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13 pages, 870 KiB

Open AccessReview

Empowering Mesenchymal Stem Cells for Ocular Degenerative Disorders

by Shirley Suet Lee Ding, Suresh Kumar Subbiah, Mohammed Safwan Ali Khan, Aisha Farhana and Pooi Ling Mok

Int. J. Mol. Sci. 2019, 20(7), 1784; https://doi.org/10.3390/ijms20071784 - 10 Apr 2019

Cited by 27 | Viewed by 5448

Abstract

Multipotent mesenchymal stem cells (MSCs) have been employed in numerous pre-clinical and clinical settings for various diseases. MSCs have been used in treating degenerative disorders pertaining to the eye, for example, age-related macular degeneration, glaucoma, retinitis pigmentosa, diabetic retinopathy, and optic neuritis. Despite [...] Read more.

Multipotent mesenchymal stem cells (MSCs) have been employed in numerous pre-clinical and clinical settings for various diseases. MSCs have been used in treating degenerative disorders pertaining to the eye, for example, age-related macular degeneration, glaucoma, retinitis pigmentosa, diabetic retinopathy, and optic neuritis. Despite the known therapeutic role and mechanisms of MSCs, low cell precision towards the targeted area and cell survivability at tissue needing repair often resulted in a disparity in therapeutic outcomes. In this review, we will discuss the current and feasible strategy options to enhance treatment outcomes with MSC therapy. We will review the application of various types of biomaterials and advances in nanotechnology, which have been employed on MSCs to augment cellular function and differentiation for improving treatment of visual functions. In addition, several modes of gene delivery into MSCs and the types of associated therapeutic genes that are important for modulation of ocular tissue function and repair will be highlighted. Full article

(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)

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14 pages, 661 KiB

Open AccessReview

The Emerging Role of Electrophiles as a Key Regulator for Endoplasmic Reticulum (ER) Stress

by Nobumasa Takasugi, Hideki Hiraoka, Kengo Nakahara, Shiori Akiyama, Kana Fujikawa, Ryosuke Nomura, Moeka Furuichi and Takashi Uehara

Int. J. Mol. Sci. 2019, 20(7), 1783; https://doi.org/10.3390/ijms20071783 - 10 Apr 2019

Cited by 12 | Viewed by 4649

Abstract

The unfolded protein response (UPR) is activated by the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which is called ER stress. ER stress sensors PERK, IRE1, and ATF6 play a central role in the initiation and regulation of the UPR; they [...] Read more.

The unfolded protein response (UPR) is activated by the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which is called ER stress. ER stress sensors PERK, IRE1, and ATF6 play a central role in the initiation and regulation of the UPR; they inhibit novel protein synthesis and upregulate ER chaperones, such as protein disulfide isomerase, to remove unfolded proteins. However, when recovery from ER stress is difficult, the UPR pathway is activated to eliminate unhealthy cells. This signaling transition is the key event of many human diseases. However, the precise mechanisms are largely unknown. Intriguingly, reactive electrophilic species (RES), which exist in the environment or are produced through cellular metabolism, have been identified as a key player of this transition. In this review, we focused on the function of representative RES: nitric oxide (NO) as a gaseous RES, 4-hydroxynonenal (HNE) as a lipid RES, and methylmercury (MeHg) as an environmental organic compound RES, to outline the relationship between ER stress and RES. Modulation by RES might be a target for the development of next-generation therapy for ER stress-associated diseases. Full article

(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response)

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12 pages, 531 KiB

Open AccessReview

Mechanisms of Adiponectin Action: Implication of Adiponectin Receptor Agonism in Diabetic Kidney Disease

by Yaeni Kim and Cheol Whee Park

Int. J. Mol. Sci. 2019, 20(7), 1782; https://doi.org/10.3390/ijms20071782 - 10 Apr 2019

Cited by 80 | Viewed by 9441

Abstract

Adiponectin, an adipokine secreted by adipocytes, exerts favorable effects in the milieu of diabetes and metabolic syndrome through its anti-inflammatory, antifibrotic, and antioxidant effects. It mediates fatty acid metabolism by inducing AMP-activated protein kinase (AMPK) phosphorylation and increasing peroxisome proliferative-activated receptor (PPAR)-α expression [...] Read more.

Adiponectin, an adipokine secreted by adipocytes, exerts favorable effects in the milieu of diabetes and metabolic syndrome through its anti-inflammatory, antifibrotic, and antioxidant effects. It mediates fatty acid metabolism by inducing AMP-activated protein kinase (AMPK) phosphorylation and increasing peroxisome proliferative-activated receptor (PPAR)-α expression through adiponectin receptor (AdipoR)1 and AdipoR2, respectively, which in turn activate PPAR gamma coactivator 1 alpha (PGC-1α), increase the phosphorylation of acyl CoA oxidase, and upregulate the uncoupling proteins involved in energy consumption. Moreover, adiponectin potently stimulates ceramidase activity associated with its two receptors and enhances ceramide catabolism and the formation of its anti-apoptotic metabolite, sphingosine 1 phosphate (S1P), independently of AMPK. Low circulating adiponectin levels in obese patients with a risk of insulin resistance, type 2 diabetes, and cardiovascular diseases, and increased adiponectin expression in the state of albuminuria suggest a protective and compensatory role for adiponectin in mitigating further renal injury during the development of overt diabetic kidney disease (DKD). We propose AdipoRon, an orally active synthetic adiponectin receptor agonist as a promising drug for restoration of DKD without inducing systemic adverse effects. Its renoprotective role against lipotoxicity and oxidative stress by enhancing the AMPK/PPARα pathway and ceramidase activity through AdipoRs is revealed here. Full article

(This article belongs to the Special Issue Mechanisms of Adiponectin Action)

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30 pages, 2227 KiB

Open AccessReview

Two Component Regulatory Systems and Antibiotic Resistance in Gram-Negative Pathogens

by Anjali Y. Bhagirath, Yanqi Li, Rakesh Patidar, Katherine Yerex, Xiaoxue Ma, Ayush Kumar and Kangmin Duan

Int. J. Mol. Sci. 2019, 20(7), 1781; https://doi.org/10.3390/ijms20071781 - 10 Apr 2019

Cited by 99 | Viewed by 12280

Abstract

Gram-negative pathogens such as Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa are the leading cause of nosocomial infections throughout the world. One commonality shared among these pathogens is their ubiquitous presence, robust host-colonization and most importantly, resistance to antibiotics. A significant [...] Read more.

Gram-negative pathogens such as Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa are the leading cause of nosocomial infections throughout the world. One commonality shared among these pathogens is their ubiquitous presence, robust host-colonization and most importantly, resistance to antibiotics. A significant number of two-component systems (TCSs) exist in these pathogens, which are involved in regulation of gene expression in response to environmental signals such as antibiotic exposure. While the development of antimicrobial resistance is a complex phenomenon, it has been shown that TCSs are involved in sensing antibiotics and regulating genes associated with antibiotic resistance. In this review, we aim to interpret current knowledge about the signaling mechanisms of TCSs in these three pathogenic bacteria. We further attempt to answer questions about the role of TCSs in antimicrobial resistance. We will also briefly discuss how specific two-component systems present in K. pneumoniae, A. baumannii, and P. aeruginosa may serve as potential therapeutic targets. Full article

(This article belongs to the Special Issue Kinase Signal Transduction 1.0)

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16 pages, 2541 KiB

Open AccessArticle

Human β-Defensin 2 Expression in Oral Epithelium: Potential Therapeutic Targets in Oral Lichen Planus

by Abdelhakim Salem, Rabeia Almahmoudi, Jaana Hagström, Holger Stark, Dan Nordström, Tuula Salo and Kari K. Eklund

Int. J. Mol. Sci. 2019, 20(7), 1780; https://doi.org/10.3390/ijms20071780 - 10 Apr 2019

Cited by 24 | Viewed by 5513

Abstract

Human β-defensin 2 (hBD-2) is a potent antimicrobial peptide that participates in defense against invading bacteria. We recently showed that bacterial components and histamine, through histamine H4 receptor (H4R), are involved in the pathogenesis of the potentially malignant lesion, oral lichen planus (OLP). [...] Read more.

Human β-defensin 2 (hBD-2) is a potent antimicrobial peptide that participates in defense against invading bacteria. We recently showed that bacterial components and histamine, through histamine H4 receptor (H4R), are involved in the pathogenesis of the potentially malignant lesion, oral lichen planus (OLP). However, the underlying mechanisms remain unknown. We, therefore, investigated the role of hBD2–histamine crosstalk signaling in promoting OLP pathology. Biopsies from OLP and oral tongue squamous cell carcinoma (OTSCC) patients, and healthy controls were used. Two OTSCC cell lines and normal human oral keratinocytes (HOKs) were used. HBD-2 and other targets were mapped by immunostaining and analyzed by ImageJ2 software. The highly sensitive droplet-digital PCR technology and qRT-PCR were utilized to study the clinically derived and in vitro samples, respectively. H4R was challenged with the specific agonist HST-10 and inverse agonist ST-1007. HBD-2 was highly induced in OLP lesions. In contrast, hBD2 expression was attenuated in OTSCC tissues, while very low levels of hBD-2 messenger RNA (mRNA) were observed in OTSCC cells. Together with tumor necrosis factor-α (TNF-α), histamine upregulated hBD-2 mRNA expression in HOKs. Activation of H4R seems to modulate the expression of epithelial hBD-2. These findings suggest the involvement of hBD-2 in the pathogenesis of OLP and may, thus, be harnessed for therapeutic interventions in OLP. Full article

(This article belongs to the Section Biochemistry)

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21 pages, 1222 KiB

Open AccessReview

MAPK/ERK Signaling in Regulation of Renal Differentiation

by Kristen Kurtzeborn, Hyuk Nam Kwon and Satu Kuure

Int. J. Mol. Sci. 2019, 20(7), 1779; https://doi.org/10.3390/ijms20071779 - 10 Apr 2019

Cited by 75 | Viewed by 15443

Abstract

Congenital anomalies of the kidney and urinary tract (CAKUT) are common birth defects derived from abnormalities in renal differentiation during embryogenesis. CAKUT is the major cause of end-stage renal disease and chronic kidney diseases in children, but its genetic causes remain largely unresolved. [...] Read more.

Congenital anomalies of the kidney and urinary tract (CAKUT) are common birth defects derived from abnormalities in renal differentiation during embryogenesis. CAKUT is the major cause of end-stage renal disease and chronic kidney diseases in children, but its genetic causes remain largely unresolved. Here we discuss advances in the understanding of how mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) activity contributes to the regulation of ureteric bud branching morphogenesis, which dictates the final size, shape, and nephron number of the kidney. Recent studies also demonstrate that the MAPK/ERK pathway is directly involved in nephrogenesis, regulating both the maintenance and differentiation of the nephrogenic mesenchyme. Interestingly, aberrant MAPK/ERK signaling is linked to many cancers, and recent studies suggest it also plays a role in the most common pediatric renal cancer, Wilms’ tumor. Full article

(This article belongs to the Special Issue ERK Signaling Pathway in Diseases)

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24 pages, 6099 KiB

Open AccessArticle

Toxic Effects of Low-Level Long-Term Inhalation Exposures of Rats to Nickel Oxide Nanoparticles

by Marina P. Sutunkova, Svetlana N. Solovyeva, Ilzira A. Minigalieva, Vladimir B. Gurvich, Irene E. Valamina, Oleg H. Makeyev, Vladimir Ya. Shur, Ekaterina V. Shishkina, Ilya V. Zubarev, Renata R. Saatkhudinova, Svetlana V. Klinova, Anastasia E. Tsaregorodtseva, Artem V. Korotkov, Eugene A. Shuman, Larisa I. Privalova and Boris A. Katsnelson

Int. J. Mol. Sci. 2019, 20(7), 1778; https://doi.org/10.3390/ijms20071778 - 10 Apr 2019

Cited by 36 | Viewed by 4750

Abstract

Rats were exposed to nickel oxide nanoparticles (NiO-NP) inhalation at 0.23 ± 0.01 mg/m³ for 4 h a day 5 times a week for up to 10 months. The rat organism responded to this impact with changes in cytological and some biochemical [...] Read more.

Rats were exposed to nickel oxide nanoparticles (NiO-NP) inhalation at 0.23 ± 0.01 mg/m³ for 4 h a day 5 times a week for up to 10 months. The rat organism responded to this impact with changes in cytological and some biochemical characteristics of the bronchoalveolar lavage fluid along with a paradoxically little pronounced pulmonary pathology associated with a rather low chronic retention of nanoparticles in the lungs. There were various manifestations of systemic toxicity, including damage to the liver and kidneys; a likely allergic syndrome as indicated by some cytological signs; transient stimulation of erythropoiesis; and penetration of nickel into the brain from the nasal mucous membrane along the olfactory pathway. Against a picture of mild to moderate chronic toxicity of nickel, its in vivo genotoxic effect assessed by the degree of DNA fragmentation in nucleated blood cells (the RAPD test) was pronounced, tending to increasing with the length of the exposure period. When rats were given orally, in parallel with the toxic exposure, a set of innocuous substances with differing mechanisms of expected bioprotective action, the genotoxic effect of NiO-NPs was found to be substantially attenuated. Full article

(This article belongs to the Special Issue Bioactive Nanoparticles)

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22 pages, 1441 KiB

Open AccessArticle

Extracellular Proteolytic Activity and Amino Acid Production by Lactic Acid Bacteria Isolated from Malaysian Foods

by Cui Jin Toe, Hooi Ling Foo, Teck Chwen Loh, Rosfarizan Mohamad, Raha Abdul Rahim and Zulkifli Idrus

Int. J. Mol. Sci. 2019, 20(7), 1777; https://doi.org/10.3390/ijms20071777 - 10 Apr 2019

Cited by 60 | Viewed by 5416

Abstract

Amino acids (AAs) are vital elements for growth, reproduction, and maintenance of organisms. Current technology uses genetically engineered microorganisms for AAs production, which has urged the search for a safer food-grade AA producer strain. The extracellular proteolytic activities of lactic acid bacteria (LAB) [...] Read more.

Amino acids (AAs) are vital elements for growth, reproduction, and maintenance of organisms. Current technology uses genetically engineered microorganisms for AAs production, which has urged the search for a safer food-grade AA producer strain. The extracellular proteolytic activities of lactic acid bacteria (LAB) can be a vital tool to hydrolyze extracellular protein molecules into free AAs, thereby exhibiting great potential for functional AA production. In this study, eight LAB isolated from Malaysian foods were determined for their extracellular proteolytic activities and their capability of producing AAs. All studied LAB exhibited versatile extracellular proteolytic activities from acidic to alkaline pH conditions. In comparison, Pediococcus pentosaceus UP-2 exhibited the highest ability to produce 15 AAs extracellularly, including aspartate, lysine, methionine, threonine, isoleucine, glutamate, proline, alanine, valine, leucine, tryptophan, tyrosine, serine, glycine, and cystine, followed by Pediococcus pentosaceus UL-2, Pediococcus acidilactici UB-6, and Pediococcus acidilactici UP-1 with 11 to 12 different AAs production detected extracellularly. Pediococcus pentosaceus UL-6 demonstrated the highest increment of proline production at 24 h of incubation. However, Pediococcus acidilactici UL-3 and Lactobacillus plantarum I-UL4 exhibited the greatest requirement for AA. The results of this study showed that different LAB possess different extracellular proteolytic activities and potentials as extracellular AA producers. Full article

(This article belongs to the Special Issue Industrial Enzymes: Structure, Function and Applications)

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22 pages, 581 KiB

Open AccessReview

Targeting Chemoresistant Tumors: Could TRIM Proteins-p53 Axis Be a Possible Answer?

by Alessio Valletti, Flaviana Marzano, Graziano Pesole, Elisabetta Sbisà and Apollonia Tullo

Int. J. Mol. Sci. 2019, 20(7), 1776; https://doi.org/10.3390/ijms20071776 - 10 Apr 2019

Cited by 34 | Viewed by 5479

Abstract

Chemosensitivity is a crucial feature for all tumours so that they can be successfully treated, but the huge heterogeneity of these diseases, to be intended both inter- and intra-tumour, makes it a hard-to-win battle. Indeed, this genotypic and phenotypic variety, together with the [...] Read more.

Chemosensitivity is a crucial feature for all tumours so that they can be successfully treated, but the huge heterogeneity of these diseases, to be intended both inter- and intra-tumour, makes it a hard-to-win battle. Indeed, this genotypic and phenotypic variety, together with the adaptability of tumours, results in a plethora of chemoresistance acquisition mechanisms strongly affecting the effectiveness of treatments at different levels. Tripartite motif (TRIM) proteins are shown to be involved in some of these mechanisms thanks to their E3-ubiquitin ligase activity, but also to other activities they can exert in several cellular pathways. Undoubtedly, the ability to regulate the stability and activity of the p53 tumour suppressor protein, shared by many of the TRIMs, represents the preeminent link between this protein family and chemoresistance. Indeed, they can modulate p53 degradation, localization and subset of transactivated target genes, shifting the cellular response towards a cytoprotective or cytotoxic reaction to whatever damage induced by therapy, sometimes in a cellular-dependent way. The involvement in other chemoresistance acquisition mechanisms, independent by p53, is known, affecting pivotal processes like PI3K/Akt/NF-κB signalling transduction or Wnt/beta catenin pathway, to name a few. Hence, the inhibition or the enhancement of TRIM proteins functionality could be worth investigating to better understand chemoresistance and as a strategy to increase effectiveness of anticancer therapies. Full article

(This article belongs to the Special Issue New Strategies to Overcome Resistance to Chemotherapy and Immune System in Cancer)

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15 pages, 3735 KiB

Open AccessArticle

Surface-Modified Biochar with Polydentate Binding Sites for the Removal of Cadmium

by Rongqi Chen, Xi Zhao, Juan Jiao, Yan Li and Min Wei

Int. J. Mol. Sci. 2019, 20(7), 1775; https://doi.org/10.3390/ijms20071775 - 10 Apr 2019

Cited by 36 | Viewed by 5424

Abstract

In this study, a surface chemical-modified rice husk biochar with abundant amino groups and disulfide bonds for the removal of cadmium was prepared using cystamine dihydrochloride as a modification ligand and glutaraldehyde as a crosslinker. The biochars were characterized by Fourier transform infrared [...] Read more.

In this study, a surface chemical-modified rice husk biochar with abundant amino groups and disulfide bonds for the removal of cadmium was prepared using cystamine dihydrochloride as a modification ligand and glutaraldehyde as a crosslinker. The biochars were characterized by Fourier transform infrared spectrometry (FTIR), elemental analysis, scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), thermogravimetry analysis (TGA), and nitrogen sorption (BET) before and after modification. The adsorption properties of the modified biochars for Cd (II) were investigated in detail via adsorption isotherm models, adsorption kinetics models, and selective adsorption experiments. The surfaces of the cystamine-modified biochars with granular nanopolymers of sufficient functional groups of primary amine and disulfide linkage rendered the biochar surface more conducive to electrostatic attraction and surface complexation. The theoretical maximum adsorption capacity of the modified biochars (81.02 mg g⁻¹) was almost 10-fold greater than that of the raw biochars (8.347 mg g⁻¹) for Cd (II). Besides, the cystamine-modified biochars had a better affinity for Cd (II) compared to other heavy metals (Zn, As, Cd, Co, Ni, Cr), showing six-fold greater affinity for Cd (II) than Zn²⁺. The results of this study indicate that the modification of biochars derived from rice husks shows great potential in the removal of Cd (II) from contaminated water. Full article

(This article belongs to the Section Materials Science)

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14 pages, 5011 KiB

Open AccessArticle

Characterization of the Chloroplast Genome of Trentepohlia odorata (Trentepohliales, Chlorophyta), and Discussion of its Taxonomy

by Huan Zhu, Yuxin Hu, Feng Liu, Zhengyu Hu and Guoxiang Liu

Int. J. Mol. Sci. 2019, 20(7), 1774; https://doi.org/10.3390/ijms20071774 - 10 Apr 2019

Cited by 10 | Viewed by 4895

Abstract

Trentepohliales is an aerial order of Chlorophyta with approximately 80 species distributed mainly in tropical and subtropical regions. The taxonomy of this genus is quite difficult and presents a challenge for many phycologists. Although plentiful molecular data is available, most of the sequences [...] Read more.

Trentepohliales is an aerial order of Chlorophyta with approximately 80 species distributed mainly in tropical and subtropical regions. The taxonomy of this genus is quite difficult and presents a challenge for many phycologists. Although plentiful molecular data is available, most of the sequences are not identified at the species level. In the present study, we described a new specimen with detailed morphological data and identified it as Trentepohlia odorata. A phylogenetic analysis showed T. odorata as a novel lineage in Trentepohliales. T. odorata has the closest relationship with T. annulata, which is expected since sporangia of both species are without stalk cell and with dorsal pore. Species with such morphological characteristics may represent deep lineages in Trentepohliales. Although an increasing number of chloroplast genomes of Ulvophyceae have been reported in recent years, the whole plastome of Trentepohliales has not yet been reported. Thus, the chloroplast genome of Trentepohlia odorata was reported in the present study. The whole plastome was 399,372 bp in length, with 63 predicted protein-coding genes, 31 tRNAs, and 3 rRNAs. Additionally, we annotated 95 free-standing open reading frames, of which seven were annotated with plastid origins, 16 with eukaryotic genome origins, and 33 with bacterial genome origins. Four rpo genes (rpoA, rpoB, rpoC1, and rpoC2) were annotated within ORF clusters. These four genes were fragmented into several (partial) ORFs by in-frame stop codons. Additionally, we detected a frame shift mutation in the rpoB gene. The phylogenetic analysis supported that Trentepohliales clustered with Dasycladales and nested into the BDT clade (Bryopsidales, Dasycladales and Trentepohliales). Our results present the first whole chloroplast genome of a species of Trentepohliales and provided new data for understanding the evolution of the chloroplast genome in Ulvophyceae. Full article

(This article belongs to the Special Issue Organelle Genetics in Plants)

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19 pages, 2888 KiB

Open AccessArticle

Allelic Diversity of Acetyl Coenzyme A Carboxylase accD/bccp Genes Implicated in Nuclear-Cytoplasmic Conflict in the Wild and Domesticated Pea (Pisum sp.)

by Eliška Nováková, Lenka Zablatzká, Jan Brus, Viktorie Nesrstová, Pavel Hanáček, Ruslan Kalendar, Fatima Cvrčková, Ľuboš Majeský and Petr Smýkal

Int. J. Mol. Sci. 2019, 20(7), 1773; https://doi.org/10.3390/ijms20071773 - 10 Apr 2019

Cited by 12 | Viewed by 4361

Abstract

Reproductive isolation is an important component of species differentiation. The plastid accD gene coding for the acetyl-CoA carboxylase subunit and the nuclear bccp gene coding for the biotin carboxyl carrier protein were identified as candidate genes governing nuclear-cytoplasmic incompatibility in peas. We examined [...] Read more.

Reproductive isolation is an important component of species differentiation. The plastid accD gene coding for the acetyl-CoA carboxylase subunit and the nuclear bccp gene coding for the biotin carboxyl carrier protein were identified as candidate genes governing nuclear-cytoplasmic incompatibility in peas. We examined the allelic diversity in a set of 195 geographically diverse samples of both cultivated (Pisum sativum, P. abyssinicum) and wild (P. fulvum and P. elatius) peas. Based on deduced protein sequences, we identified 34 accD and 31 bccp alleles that are partially geographically and genetically structured. The accD is highly variable due to insertions of tandem repeats. P. fulvum and P. abyssinicum have unique alleles and combinations of both genes. On the other hand, partial overlap was observed between P. sativum and P. elatius. Mapping of protein sequence polymorphisms to 3D structures revealed that most of the repeat and indel polymorphisms map to sequence regions that could not be modeled, consistent with this part of the protein being less constrained by requirements for precise folding than the enzymatically active domains. The results of this study are important not only from an evolutionary point of view but are also relevant for pea breeding when using more distant wild relatives. Full article

(This article belongs to the Special Issue Legume Genetics and Biology: From Mendel's Pea to Legume Genomics)

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Int. J. Mol. Sci., Volume 20, Issue 7 (April-1 2019) – 282 articles

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